HDAC inhibitor

ABSTRACT

A compound having the following formula (I):  
                 
 
     wherein  
     R 1  is N-containing heterocyclic ring optionally substituted with one or more suitable substituent(s),  
     R 2  is hydroxyamino,  
     R 3  is hydrogen or a suitable substituent,  
     L 1  is —(CH 2 ) n — (wherein n is an integer of 0 to 6) optionally substituted with one or more suitable substituent(s), wherein one or more methylene(s) may be replaced with suitable heteroatom(s), and  
     L 2  is lower alkenylene,  
     or a salt thereof. The compound is useful as a histone deacetylase inhibitor.

TECHNICAL FIELD

[0001] The present invention relates to a compound useful as amedicament, and to a pharmaceutical composition comprising the same.

BACKGROUND ART

[0002] Histone deacetylase (hereinafter also referred as HDAC) is knownto play an essential role in the transcriptional machinery forregulating gene expression, induce histone hyperacetylation and toaffect the gene expression. Therefore, it is useful as a therapeutic orprophylactic agent for diseases caused by abnormal gene expression suchas inflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infections,tumors, etc.

[0003] WO 01/38322 discloses an inhibitor of histone deacetylaserepresented by the following formula:

Cy-L¹-Ar—Y¹—C(O)—NH-Z

[0004] wherein

[0005] Cy is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of whichis optionally substituted;

[0006] L¹ is —(CH₂)_(m)—W— wherein m is an integer of 0 to 4, and W isselected from the group consisting of —C(O)NH—, —S(O)₂NH—, etc.;

[0007] Ar is optionally substituted arylene, which is optionally fusedto an aryl, heteroaryl ring, etc.;

[0008] Y¹ is a chemical bond or a straight- or branched-chain saturatedalkylene, wherein said alkylene is optionally substituted; and

[0009] Z is selected from the group consisting of anilinyl, pyridyl,thiadiazolyl and —O-M wherein M is H or a pharmaceutically acceptablecation.

[0010] WO 02/22577 discloses the following hydroxamate compound as adeacetylase inhibitor:

[0011] wherein

[0012] R₁ is H, halo or a straight chain C₁-C₆ alkyl;

[0013] R₂ is selected from H, C₁-C₁₀ alkyl, C₄-C₉ cycloalkyl, C₄-C₉heterocycloalkyl, C₄-Cg heterocycloalkylalkyl, cycloalkylalkyl, aryl,heteroaryl, etc.;

[0014] R₃ and R₄ are the same or different and independently H, C₁-C₆alkyl, acyl or acylamino, or

[0015] R₃ and R₄ together with the carbon to which they are bound torepresent C═O, C═S, etc., or

[0016] R₂ together with the nitrogen to which it is bound and R₃together with the carbon to which it is bound to form a C₄-C₉heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromaticpolyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;

[0017] R₅ is selected from H, C₁-C₆ alkyl, etc.; n, n₁, n₂ and n₃ arethe same or different and independently selected from 0-6, when n₁ is1-6, each carbon atom can be optionally and independently substitutedwith R₃ and/or R₄;

[0018] X and Y are the same or different and independently selected fromH, halo, C₁-C₄ alkyl, etc.;

[0019] or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

[0020] The present invention relates to a novel compound useful as amedicament, and to a pharmaceutical composition comprising the same.

[0021] More particularly, the present invention relates to a compoundhaving a potent inhibitory effect on the activity of histonedeacetylase.

[0022] The inventors of the present invention have also found thathistone deacetylase inhibitors, such as a compound of the formula (I)(hereinafter compound [I]), have a potent immunosuppressive effect andpotent antitumor effect. Therefore, a histone deacetylase inhibitorssuch as compound [I] is useful as an active ingredient for animmunosuppressant and an antitumor agent, and useful as an activeingredient for a therapeutic or prophylactic agent for diseases such asinflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infections,tumors, etc.

[0023] Accordingly, one object of the present invention is to provide acompound having biological activities for treating or preventing thediseases as stated above.

[0024] A further object of the present invention is to provide apharmaceutical composition containing the compound [I] as an activeingredient.

[0025] A yet further object of the present invention is to provide useof the histone deacetylase inhibitors, such as compound [I], fortreating and preventing the diseases as stated above.

[0026] A yet further object of the present invention is to provide acommercial package comprising the pharmaceutical composition containingthe compound [I] and a written matter associated therewith, the writtenmatter stating that the pharmaceutical composition may or should be usedfor treating or preventing the diseases as stated above.

[0027] Thus, the present invention provides

[0028] [1] A compound having the following formula (I):

[0029]  wherein

[0030] R¹ is N-containing heterocyclic ring optionally substituted withone or more suitable substituent(s),

[0031] R² is hydroxyamino,

[0032] R³ is hydrogen or a suitable substituent,

[0033] L¹ is —(CH₂)_(n)— (wherein n is an integer of 0 to 6) optionallysubstituted with one or more suitable substituent(s), wherein one ormore methylene(s) may be replaced with suitable heteroatom(s), and

[0034] L² is lower alkenylene,

[0035] or a salt thereof.

[0036] [2] The compound of the above-mentioned [1], wherein

[0037] R¹ is N-containing heterocyclic ring represented by the followingformula:

[0038]  wherein

[0039] R⁴ is hydrogen or a group selected from the group consisting of

[0040] (1) lower alkyl optionally substituted with di(lower)alkylaminoor hydroxy,

[0041] (2) lower alkoxy,

[0042] (3) aryl optionally substituted with the substituent selectedfrom the group consisting of halogen, lower alkanoyl, loweralkylsulfonyl, lower alkoxy and di(lower)alkylamino,

[0043] (4) lower alkanoyl,

[0044] (5) lower alkoxy-carbonyl,

[0045] (6) arylcarbonyl,

[0046] (7) aryl(lower)alkoxy,

[0047] (8) amino optionally mono- or di-substitited with substituent(s)selected from the group consisting of lower alkyl, lower alkanoyl andcycloalkyl,

[0048] (9) halo(lower)alkyl,

[0049] (10) aryloxy,

[0050] (11) aryl(lower)alkyl optionally substituted with hydroxy,

[0051] (12) carboxyl,

[0052] (13) nitro,

[0053] (14) cyano,

[0054] (15) halogen,

[0055] (16) heteroaryl,

[0056] (17) non-aromatic heterocycle optionally substituted with loweralkyl,

[0057] (18) hydroxy,

[0058] (19) (lower)alkylsulfonylcarbamoyl and

[0059] (20) non-aromatic heterocycle carbonyl,

[0060] R⁵ is hydrogen or a group selected from the group consisting oflower alkyl and aryl(lower)alkyl, and

[0061] R⁶, R⁷ and R⁸ are each hydrogen or lower alkyl,

[0062] R⁹ is hydrogen or a group selected from the group consisting of

[0063] (1) lower alkyl optionally substituted with di(lower)alkylamino,

[0064] (2) aryl optionally substituted with lower alkoxy,

[0065] (3) (lower)alkoxy-carbonyl,

[0066] (4) cyano,

[0067] (5) carbamoyl optionally mono- or di-substituted with(lower)alkyl,

[0068] (6) halogen,

[0069] (7) (lower)alkyl-carbonyl,

[0070] (8) arylcarbonyl and

[0071] (9) cyclo(lower)alkyl,

[0072] R¹⁰ is hydrogen or a group selected from the group consisting of

[0073] (1) (lower)alkylcarbamoyl,

[0074] (2) di(lower)alkylcarbamoyl,

[0075] (3) aryl optionally substituted with halogen,

[0076] (4) (lower)alkoxy-carbonyl,

[0077] (5) carboxy,

[0078] (6) non-aromatic heterocycle carbonyl,

[0079] (7) halogen,

[0080] (8) (lower)alkyl optionally substituted with hydroxy,(lower)alkoxy, non-aromatic heterocycle, aryl, di(lower)alkylamino orhalogen and

[0081] (9) adamantyl,

[0082] R¹¹ is hydrogen or aryl(lower)alkyl in which the aryl portion issubstituted with lower alkoxy,

[0083] R¹² is hydrogen or a group selected from the group consisting oflower alkyl and aryl optionally substituted with halogen,

[0084] R¹³ is hydrogen or a group selected from the group consisting oflower alkyl and aryl, and

[0085] R¹⁴ is hydrogen or lower alkyl,

[0086] R² is hydroxyamino,

[0087] R³ is hydrogen or lower alkoxy,

[0088] L¹ is —(CH₂)_(n)— (wherein n is 1 to 5) optionally substitutedwith one or more substituent(s) selected from lower alkyl(s) andaryl(lower)alkyl, and wherein one methylene may be replaced with anoxygen atom, and

[0089] L² is vinylene, or a salt thereof.

[0090] [3] The compound of the above-mentioned [2], wherein

[0091] R¹ is N-containing condensed heterocyclic ring represented by thefollowing formula:

[0092]  wherein R⁴ and R⁵ are each as defined in the above-mentioned[2].

[0093] [4] The compound of the above-mentioned [3], wherein

[0094] R⁴ and R⁵ are each hydrogen,

[0095] R² is hydroxyamino,

[0096] R³ is hydrogen,

[0097] L¹ is —CH₂—, and

[0098] L² is vinylene,

[0099] or a salt thereof.

[0100] [5] The compound of the above-mentioned [2], wherein

[0101] R¹ is N-containing heterocyclic ring represented by the followingformula:

[0102]  wherein R⁹, R¹⁰ and R¹¹ are each as defined in theabove-mentioned [2].

[0103] [6] The compound of the above-mentioned [5], wherein

[0104] R⁹ is hydrogen or aryl optionally substituted with lower alkoxy,

[0105] R¹⁰ is hydrogen or aryl optionally substituted with halogen, and

[0106] R¹¹ is hydrogen,

[0107] R² is hydroxyamino,

[0108] R³ is hydrogen,

[0109] L¹ is —CH₂—, and

[0110] L² is vinylene,

[0111] or a salt thereof.

[0112] [7] A compound of the following formula

[0113] or a salt thereof.

[0114] [8] A compound having the following formula (I⁵):

[0115]  wherein

[0116] R¹ is N-containing condensed heterocyclic ring optionallysubstituted with one or more suitable substituent(s),

[0117] R² is hydroxyamino,

[0118] R³ is hydrogen or a suitable substituent,

[0119] L¹ is —(CH₂)_(n)— (wherein n is an integer of 0 to 6) optionallysubstituted with one or more suitable substituent(s), wherein one ormore methylene(s) may be replaced with suitable heteroatom(s), and

[0120] L² is lower alkenylene,

[0121] or a salt thereof.

[0122] [9] The compound of the above-mentioned [8], wherein

[0123] R¹ is N-containing condensed heterocyclic ring represented by thefollowing formula:

[0124]  wherein

[0125] R⁴ is hydrogen or a group selected from the group consisting of

[0126] (1) lower alkyl,

[0127] (2) lower alkoxy,

[0128] (3) aryl optionally substituted with the substituent selectedfrom the group consisting of halogen, lower alkanoyl, loweralkylsulfonyl, lower alkoxy and di(lower)alkylamino,

[0129] (4) lower alkanoyl,

[0130] (5) lower alkoxy-carbonyl,

[0131] (6) arylcarbonyl,

[0132] (7) aryl(lower)alkoxy,

[0133] (8) amino optionally mono- or di-substitited with substituent(s)selected from the group consisting of lower alkyl, lower alkanoyl andcycloalkyl,

[0134] (9) halo(lower)alkyl,

[0135] (10) aryloxy,

[0136] (11) aryl(lower)alkyl optionally substituted with hydroxy,

[0137] (12) carboxyl,

[0138] (13) nitro,

[0139] (14) cyano,

[0140] (15) halogen,

[0141] (16) heteroaryl and

[0142] (17) non-aromatic heterocycle optionally substituted with loweralkyl,

[0143] R⁵ is hydrogen or a group selected from the group consisting oflower alkyl and aryl(lower)alkyl, and

[0144] R⁶, R? and R⁸ are each hydrogen or lower alkyl,

[0145] R² is hydroxyamino,

[0146] R³ is hydrogen or lower alkoxy,

[0147] L¹ is —(CH₂)_(n)— (wherein n is 1 or 2) optionally substitutedwith one or more substituent(s) selected from lower alkyl(s) andaryl(lower)alkyl, and wherein one methylene may be replaced with anoxygen atom, and

[0148] L² is vinylene,

[0149] or a salt thereof.

[0150] [10] A compound having the following formula (I″):

[0151]  wherein

[0152] R¹ is N-containing condensed heterocyclic ring optionallysubstituted with one or more suitable substituent(s),

[0153] R² is hydroxyamino,

[0154] L¹ is —(CH₂)_(n)— (wherein n is an integer of 0 to 6) optionallysubstituted with one or more suitable substituent(s), and

[0155] L² is lower alkenylene,

[0156] or a salt thereof.

[0157] [11] The compound of the above-mentioned [10], wherein

[0158] R¹ is N-containing condensed heterocyclic ring represented by thefollowing formula:

[0159]  wherein

[0160] R⁴ is hydrogen or a group selected from the group consisting oflower alkyl and aryl, and

[0161] R⁵ is hydrogen or a group selected from the group consisting oflower alkyl and aryl(lower)alkyl,

[0162] R² is hydroxyamino,

[0163] L¹ is —(CH₂)_(n)— (wherein n is 1 or 2) optionally substitutedwith aryl(lower)alkyl, and

[0164] L² is vinylene,

[0165] or a salt thereof.

[0166] Of the above-mentioned compounds, the compounds represented bythe general formulas (I′) and (I″) are also encompassed in the scope ofthe compound represented by the general formula (I). Hereinafter“compound (I)” also encompasses “compound (I′)” and “compound (I″)”.

[0167] The above-mentioned compounds and salts thereof can be preparedby the processes as illustrated in the following reaction schemes or bythe methods disclosed in the Preparations and Examples.

[0168] In the above and subsequent descriptions of the presentspecification, suitable examples and illustration of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows.

[0169] In the following Processes, the compound [I-1] and [I-2] areencompassed in the scope of the compound [I], and the compound [II-A],[II-B], [II-C], [II-C′], [II-D], [II-E], [II-F], [II-G[, [II-H], [II-I],[II-J], [II-K], [II-L], [II-M] and [II-N]are also encompassed in thescope of the compound [II].

[0170] wherein

[0171] R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹³, L¹ and L²are as defined above,

[0172] Hal and Hal′ are each halogen,

[0173] L^(1′) is L¹ in which one of the carbon atoms is substituted withR⁵ (wherein R⁵ is as defined above),

[0174] R¹⁵ and R¹⁶ are each lower alkyl (e.g., alkyl having 1 to 6carbon atom(s) such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl,hexyl, etc.), or R¹⁵, R¹⁶ and the nitrogen atom to which they areattached may be together to form non-aromatic heterocycle in which oneor more carbon(s) of said heterocycle is(are) optionally replaced withone or more heteroatom(s) selected from oxygen, nitrogen and sulfur(e.g., piperidino, morpholino, etc.), and

[0175] R^(a) is a hydroxy protecting group.

[0176] In the above-mentioned Processes A, B, C, D, E, F, G, H, I, J, K,L, M and N, each of the starting compounds can be prepared, for example,according to the procedures as illustrated in Preparations in thepresent specification or in a manner similar thereto.

[0177] For example, compounds (A-1), (A-2), (A-3) and (A-4) can beobtained by the procedures as illustrated in Preparations 1, 2, 3 and 4respectively; compounds (B-1), (B-2) and (B-3) can be obtained by theprocedures as illustrated in Preparations 6, 7 and 8 respectively;compound (C-1) and (C-1′) can be obtained by the procedure asillustrated in Preparation 10; compound (C-2) and (C-3) can be obtainedby the procedure as illustrated in Preparations 11 and 12 respectively;compound (C-2′) and (C-3′) can be obtained by the procedure asillustrated in Preparations 23 and 24 respectively; compound (D-1) and(D-2) can be obtained by the procedure as illustrated in Preparations 20and 21 respectively; compound (E-1) can be obtained by the procedure asillustrated in Preparation 35; compounds (F-1), (F-2), (F-3), (F-4) and(F-5) can be obtained by the procedures as illustrated in Preparations127, 128, 129, 130 and 131, respectively; compounds (G-1) and (G-2) canbe obtained by the procedures as illustrated in Preparations 195 and196, respectively; compounds (H-1), (H-2) and (H-3) can be obtained bythe procedures as illustrated in Preparations 204, 206 and 201,respectively; compounds (1-1) and (1-2) can be obtained by theprocedures as illustrated in Preparations 212 and 219, respectively;compound (J-1) can be obtained by the procedure as illustrated inPreparation 226; Compound (K-1) can be obtained by the procedure asillustrated in Preparation 293; Compound (L-1) can be obtained by theprocedure as illustrated in Preparation 294; Compounds (M-1) and (M-2)can be obtained by the procedures illustrated in Preparations 101 and102; and Compounds (N-1) and (N-2) can be obtained by the proceduresillustrated in Preparations 233 and 249. The compounds [II-A], [II-B],[II-C], [II-C′], [II-D], [II-E], [II-F], can be obtained, for example,by the procedures as illustrated in Preparations 5, 9, 13, 25, 22, 39,132, 197, 208, 222, 191, 282, 284, 103 and 189, respectively.

[0178] The compound [I] of the present invention is obtained fromcompound [II], for example, according to the following processes ormethods disclosed in the Examples.

[0179] wherein R¹, R², R³, L¹, L² and R^(a) are as defined above.

[0180] Process 1

[0181] The compound [I-1] is obtained as an acid addition salt bydeprotecting the hydroxy group of the compound [II] in the presence ofan acid.

[0182] The acid includes such as hydrogen chloride solution (e.g.hydrogen chloride in solvent such as methanol, dioxane, ethyl acetate,diethyl ether, etc.), acetic acid, p-toluenesulfonic acid, boric acid,etc.

[0183] Optionally, one or more suitable solvent(s) for the deprotectionis(are) used. Such solvent includes such as methanol, ethanol, ethylacetate, dioxane, diethyl ether, acetic acid, etc.

[0184] The temperature of the reaction is not critical, and the reactionis usually carried out from under cooling to heating.

[0185] This Process is exemplified by Examples 1, 58, etc.

[0186] Process 2

[0187] The compound [I-2] is obtained as a free form by reacting theabove-mentioned compound [I-1], which is an acid salt addition salt,with a base.

[0188] Suitable base includes such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, aqueous sodium hydrogen carbonatesolution, aqueous potassium hydrogen carbonate solution, aqueous sodiumhydroxide solution, etc.

[0189] Optionally, one or more suitable solvent(s) for the deprotectionis(are) used for this reaction. Such solvent includes such as methanol,ethanol, ethyl acetate, dioxane, diethyl ether, acetic acid, etc.

[0190] The temperature of the reaction is not critical, and the reactionis usually carried out from under cooling to heating.

[0191] This Process is exemplified by Examples 116, etc.

[0192] Furthermore, the compound [I-2] can be converted to a suitablesalt, which is also encompassed in the scope of the present invention,by a conventional method or the methods explained in the presentspecification (e.g., Examples 113, 118, 119, 120, 123, etc.).

[0193] The compound [I] may be a salt, which is also encompassed in thescope of the present invention. For example, when a basic group such asan amino group is present in a molecule, the salt is exemplified by anacid addition salt (e.g. salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, etc., salt with anorganic acid such as methanesulfonic acid, benzenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid (e.g.,[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acidor an enantiomer thereof, etc.), fumaric acid, maleic acid, mandelicacid, citric acid, salicylic acid, malonic acid, glutaric acid, succinicacid, etc.), etc., and when an acidic group such as carboxyl group ispresent, the salt is exemplified by a basic salt (e.g. salt with a metalsuch as lithium, sodium, potassium, calcium, magnesium, aluminium, etc.,a salt with amino acid such as lysine, etc.), etc.

[0194] In addition, solvates of the compound [I] such as hydrate,ethanolate, etc., are also encompassed in the scope of the presentinvention.

[0195] When the compound [I] has stereoisomers, such isomers are alsoencompassed in the scope of the present invention.

[0196] In the above and subsequent descriptions of the presentspecification, suitable examples and illustration of the variousdefinitions which the present invention intends to include within thescope thereof are explained in detail as follows.

[0197] Each of the terms “halogen”, “halo” and “Hal” includes fluorine,chlorine, bromine and iodine.

[0198] The term “heteroatom” includes nitrogen atom, oxygen atom andsulfur atom.

[0199] The term “lower” used in the description is intended to mean 1 to6 carbon atom(s) unless otherwise indicated.

[0200] Suitable “one or more” includes the number of 1 to 6, preferably1 to 3.

[0201] Suitable “lower alkyl” includes straight or branched alkyl having1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, hexyl,isohexyl, etc.

[0202] Suitable “cyclo(lower)alkyl” includes cycloalkyl having 3 to 6carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,etc.

[0203] Suitable “lower alkoxy” includes straight or branched alkoxyhaving 1 to 6 carbon atom(s) such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc.

[0204] Suitable “lower alkanoyl” includes formyl and alkanoyl in whichthe alkyl portion is straight or branched alkyl having 1 to 6 carbonatom(s) such as acetyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl,tert-butylcarbonyl, pentylcarbonyl, tert-pentylcarbonyl,neopentylcarbonyl, hexylcarbonyl, isohexylcarbonyl, etc.

[0205] Suitable “lower alkoxy-carbonyl” includes alkoxycarbonyl in whichthe alkyl portion is straight or branched alkyl having 1 to 6 carbonatom(s) such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,tert-pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl,isohexyloxycarbonyl, etc.

[0206] Suitable “halo(lower)alkyl” includes lower alkyl substituted with1 to 3 halogen atom(s) such as monochloromethyl, dichloromethyl,trichloromethyl, monofluoromethyl, difluoromethyl, trifluoromethyl,monobromomethyl, dibromomethyl, tribromomethyl, monochloroethyl,dichloroethyl, trichloroethyl, monofluoroethyl, difluoroethyl,trifluoroethyl, etc.

[0207] Suitable “lower alkenylene” includes straight or branchedalkylene having 1 to 6 carbon atom(s) such as vinylene,1-methylvinylene, 2-methylvinylene, 1-propenylene, 2-propenylene,2-methyl-1-propenylene, 2-methyl-2-propenylene, 1-butenylene,2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene,4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexenylene,5-hexenylene, etc. Suitable lower alkenylene for L² is, for example,vinylene, 1-methylvinylene, 2-methylvinylene, etc.

[0208] Suitable “aryl” includes C₆-C₁₆ aryl such as phenyl, naphthyl,anthryl, pyrenyl, phenanthryl, azulenyl, etc.

[0209] Suitable “aryloxy” includes C₆-C₁₆ aryloxy such as phenoxy,naphthyloxy, anthryloxy, pyrenyloxy, phenanthryloxy, azulenyloxy, etc.

[0210] Suitable “aryl(lower)alkyl” includes phenyl(C₁-C₆)alkyl such asbenzyl, phenethyl, phenylpropyl, phenylbutyl, phenylhexyl, etc.,naphthyl(C₁-C₆)alkyl such as naphthylmethyl, naphthylethyl,naphthylpropyl, naphthylbutyl, naphthylpentyl, naphtylhexyl, etc.

[0211] Suitable “arylcarbonyl” includes arylcarbonyl in which the arylportion is C₆-C₁₆ aryl such as phenylcarbonyl (benzoyl),naphthylcarbonyl, anthrylcarbonyl, pyrenylcarbonyl, phenanthrylcarbonyl,azulenylcarbonyl, etc.

[0212] Suitable “aryl(lower)alkoxy” includes phenyl(C₁-C₆)alkoxy such asbenzyloxy, phenethyloxy, phenylpropyloxy, phenylbutyloxy,phenylhexyloxy, etc., naphthyl(C₁-C₆)alkyloxy such as naphthylmethyloxy,naphthylethyloxy, naphthylpropyloxy, naphthylbutyloxy,naphthylpentyloxy, naphtylhexyloxy, etc.

[0213] Suitable “amino” includes unsubstituted amino, and amino mono- ordi-substituted with substituent(s) selected from lower alkyl, loweralkanoyl and cycloalkyl such as N-(C₁-C₆ alkyl)amino (e.g.,N-methylamino, N-ethylamino, N-propylamino, N-(n-butyl)amino,N-isobutylamino, N-(t-butyl)amino, etc.), N-(C₁-C₆ alkanoyl)amino (e.g.,N-acetylamino, N-ethylcarbonylamino, N-propylcarbonylamino,N-(n-butylcarbonyl)amino, N-isobutylcarbonylamino, N-(t-butylcarbonyl)amino, etc.), N-(C₃-C₆ cycloalkyl)amino. (e.g., N-cyclopropylamino,N-cyclobutylamino, N-cyclopentylamino, N-cyclohexylamino, etc.), N,N-di(C₁-C₆ alkyl)amino (e.g., N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, etc.), etc.

[0214] Suitable “carbamoyl optionally mono- or di-substituted with loweralkyl(s)” includes carbamoyl; N-(lower)alkylcarbamoyl in which the alkylportion is alkyl having 1 to 6 carbon atom(s) such as N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl,N-isobutylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl,N-neopentylcarbamoyl, N-isopentylcarbamoyl, N-hexylcarbamoyl, etc.;N,N-di(lower)alkylcarbamoyl in which the alkyl portions are each alkylhaving 1 to 6 carbon atom(s) such as N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl,N,N-diisobutylcarbamoyl, N,N-di-tert-butylcarbamoyl,N,N-dipentylcazbamoyl, N,N-dineopentylcarbamoyl,N,N-diisopentylcarbamoyl, N,N-dihexylcarbamoyl,N-ethyl-N-methylcarbamoyl, N-methyl-N-propylcarbamoyl,N-butyl-N-methylcarbamoyl, N-methyl-N-isobutylcarbamoyl, etc.

[0215] The “heteroaryl” includes groups having 5 to 14 ring atoms and πelectrons shared in a cyclic array and containing 1 to 4 heteroatomsselected from the group consisting of nitrogen, oxygen and sulfurbesides carbon atoms. Suitable “heteroaryl” includes such as thienyl,benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl,pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl,isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl,etc.

[0216] The “heteroaryl” and “(lower)alkyl” of the“heteroaryl(lower)alkyl” are similar to those exemplified for the“heteroaryl” and “(lower)alkyl” respectively. Suitable“heteroaryl(lower)alkyl” includes pyridylmethyl, pyridylethyl,quinolylmethyl, etc.

[0217] Each of the two “(lower)alkyl” of the“(lower)alkyl-carbonyl(lower)alkyl” is similar to that exemplified forthe “(lower)alkyl”. Suitable “(lower)alkyl-carbonyl (lower)alkyl”includes acetylmethyl, ethylcarbonylmethyl, etc.

[0218] The “non-aromatic heterocycle” includes group having 5 to 14 ringatoms and containing 1 to 3 heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur besides carbon atoms. Suitable“non-aromatic heterocycle” includes such as pyrrolidinyl, pyrazolidinyl,imidazolidinyl, isoxazolidinyl, isothiazolidinyl, piperidyl (e.g.,piperidino etc.), piperazinyl, morpholinyl (e.g., morpholino etc.),thiomorpholinyl (e.g., thiomorpholino etc.), etc.

[0219] Suitable “N-containing heterocyclic ring” for the “N-containingheterocyclic ring optionally substituted with one or moresubstituent(s)” includes N-containing condensed heterocyclic ring suchas indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl(e.g., imidazo[4,5-c]pyridyl, etc.), tetrahydroimidazopyridyl (e.g.,4,5,6,7-tetrahydro[4,5-c]pyridyl, etc.), 7-azabicyclo[2.2.1]heptyl,3-azabicyclo[3.2.2]nonanyl, pyridoimidazolyl (e.g.pyrido[3,2-d]imidazolyl, pyrido[4,3-d]imidazolyl, etc.),azabenzimidazolyl, etc., and N-containing heteroaryl ring such asimidazolyl, thiazolyl, pyrazolyl, oxazolyl, etc.

[0220] Specifically, the preferred N-containing heterocyclic ringoptionally substituted with one or more substituent(s) represented by R¹includes, for example, the groups represented by the following formula

[0221] wherein R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are asdefined above.

[0222] In the above formulas, R⁴ is hydrogen or a group such as (1)lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl,hexyl, etc.); (2) lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, etc.); (3) aryl optionally substituted with thesubstituent selected from the group consisting of halogen, loweralkanoyl, lower alkylsulfonyl, lower alkoxy and di(lower)alkylamino(e.g., phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-acetylphenyl,4-(N,N-dimethylamino)phenyl, 4-fluorophenyl, 4-methylsulfonylphenyl,etc.); (4) lower alkanoyl (e.g., acetyl, etc.); (5) loweralkoxy-carbonyl (e.g., methoxycarbonyl, etc.); (6) arylcarbonyl (e.g.,benzylcarbonyl, etc.); (7) aryl(lower)alkoxy (e.g., benzyloxy, etc.);(8) amino optionally mono- or di-substitited with substituent(s)selected from the group consisting of lower alkyl, lower alkanoyl andcycloalkyl (e.g., amino, N,N-dimethylamino, N,N-diethylamino,N-propylcarbonylamino, N-cyclopentylamino, etc.); (9) halo(lower)alkyl(e.g., trifluoromethyl, etc.); (10) aryloxy (e.g., phenoxy, etc.); (11)aryl(lower)alkyl optionally substituted with hydroxy (e.g.,hydroxyphenylmethyl, etc.); (12) carboxyl; (13) nitro; (14) cyano; (15)halogen (e.g., fluorine, chlorine, bromine, etc.); (16) heteroaryl(e.g., thienyl, tetrazolyl, pyridyl, etc.); (17) non-aromaticheterocycle optionally substituted with lower alkyl (e.g.,4-methylpiperadinyl, morpholino, piperidino, etc.); (18) hydroxy,

[0223] (19) (lower)alkylsulfonylcarbamoyl (e.g.,methylsulfonylcarbamoyl, etc.), (20) non-aromatic heterocycle carbonyl(e.g., pyrrolidin-1-ylcarbonyl, etc.). Furthermore,heteroaryl(lower)alkyl (e.g. pyridyl(lower)alkyl such as pyridylmethyl,etc.), lower alkyl-carbonyl(lower)alkyl (e.g. acetylmethyl, etc.), etc.can be also used for R⁴.

[0224] In the above formulas, R⁵ is hydrogen or a group selected fromthe group consisting of lower alkyl (e.g. methyl, ethyl, propyl, butyl,etc.), aryl(lower)alkyl(e.g. benzyl, phenetyl, etc.),heteroaryl(lower)alkyl (e.g. pyridyl(lower)alkyl such as pyridylmethyl,etc.) and lower alkyl-carbonyl(lower)alkyl (e.g. acetylmethyl, etc.).Preferably, R⁵ is hydrogen or a group selected from the group consistingof lower alkyl and aryl(lower)alkyl.

[0225] In the above formulas, R⁶, R⁷ and R⁸ are each hydrogen or loweralkyl (e.g. methyl, ethyl, propyl, butyl, etc.) In the above formulas,R⁹ is hydrogen or a group such as (1) lower alkyl optionally substitutedwith di(lower)alkylamino (e.g., dimethylaminoethyl, etc.); (2) aryloptionally substituted with lower alkoxy (e.g., phenyl, o-methoxyphenyl,m-methoxyphenyl, p-methoxyphenyl, etc.); (3)(lower)alkoxy-carbonyl(e.g., methoxycarbonyl, etc.); (4) cyano; (5) carbamoyl optionally mono-or di-substituted with (lower)alkyl (e.g., carbamoyl,N,N-dimethylcarbamoyl, N-isopropylcarbamoyl, etc.); (6) halogen (e.g.,chloro, bromo, etc.); (7) (lower)alkyl-carbonyl (e.g., acetyl, etc.);(8) arylcarbonyl (e.g., benzoyl, etc.); (9) cyclo(lower)alkyl (e.g.,cyclohexyl, etc.), etc.

[0226] In the above formulas, suitable substituent represented by R¹⁰ ishydrogen or a group such as (1) (lower)alkylcarbamoyl (e.g.,N-methylcarbamoyl, etc.); (2) di(lower)alkylcarbamoyl (e.g.,N,N-dimethylcarbamoyl, etc.); (3) aryl optionally substituted withhalogen (e.g., phenyl, p-chlorophenyl, p-fluorophenyl, etc.); (4)(lower)alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.);(5) carboxy; (6) non-aromatic heterocycle carbonyl (e.g.,piperidinylcarbonyl, etc.); (7) halogen (e.g., chloro, etc.); (8)(lower)alkyl optionally substituted with hydroxy or (lower)alkoxy,non-aromatic heterocycle, aryl, di(lower)alkylamino or halogen (e.g.,hydroxymethyl, methoxymethyl, piperidinomethyl, morpholinomethyl,N,N-dimethylaminomethyl, trifluoromethyl, etc.); and (9) adamantyl, etc.

[0227] In the above formulas, suitable substituent represented by R¹¹ ishydrogen or aryl(lower)alkyl in which the aryl portion is substitutedwith lower alkoxy (e.g., p-methoxyphenylmethyl, etc.), etc.

[0228] In the above formulas, suitable substituent represented by R¹² ishydrogen or a group selected from lower alkyl (e.g., methyl, etc.), aryloptionally substituted with halogen (e.g., phenyl, p-chlorophenyl,etc.), etc.

[0229] In the above-formulas, suitable substituent represented by R¹³ ishydrogen or a group selected from lower alkyl (e.g., methyl, etc.), aryl(e.g., phenyl, etc.), etc.

[0230] In the above formulas, suitable substituent represented by R¹⁴ ishydrogen or lower alkyl (e.g., methyl, etc.), etc.

[0231] Suitable “n” of the “—(CH₂)_(n)—” for L¹ is an integer of 0 to 6,preferably 1 or 2. The “—(CH₂)_(n)—” is optionally substituted with oneor more suitable substituent(s) such as lower alkyl (e.g. methyl, ethyl,propyl, butyl, pentyl, hexyl, etc.), lower alkoxy (e.g. methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, etc.), aryl(lower)alkyl (e.g.benzyl, etc.), etc. Furthermore, one or more methylenes (e.g., onemethylene, etc.) may be replaced with suitable heteroatoms (e.g., oxygenatom, etc.).

[0232] Suitable “—(CH₂)_(n)—” for L¹ of the present invention includes,for example, —CH₂—, —(CH₂)₂—, —CH(CH₃)—, —CH₂—O—, —(CH₂)₃—, —(CH₂)₃—O—,—(CH₂)₄—O—,

[0233] etc.

[0234] Suitable “hydroxy protecting group” is as follows:

[0235] lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, etc.), preferably methyl;

[0236] lower alkoxy(lower)alkyl (e.g. methoxymethyl, etc.); loweralkoxy(lower)alkoxy(lower)alkyl (e.g. 2-methoxyethoxymethyl, etc.);

[0237] ar(lower)alkyl in which the aryl portion is optionallysubstituted with one or more suitable substituent(s) (e.g. benzyl (Bn),p-methoxybenzyl, m,p-dimethoxybenzyl, etc.), preferably benzyl;

[0238] ar(lower)alkoxy(lower)alkyl in which the aryl portion isoptionally substituted with one or more suitable substituent(s) (e.g.benzyloxymethyl, p-methoxybenzyloxymethyl, etc.);

[0239] (lower)alkylthio(lower)alkyl (e.g. methylthiomethyl,ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl,isobutylthiomethyl, hexylthiomethyl, etc.), etc., preferablymethylthiomethyl;

[0240] trisubstituted silyl such as tri(lower)alkylsilyl (e.g.trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl,tri-tert-butylsilyl, etc.), lower alkyldiarylsilyl (e.g.methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl,tert-butyldiphenylsilyl (TBDPS), etc.), etc., preferablytert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl;

[0241] heterocyclic group (e.g. tetrahydropyranyl, etc.); acyl asdescribed below [e.g. aliphatic acyl such as lower alkanoyl (e.g.acetyl, propanoyl, pivaloyl, etc.); aromatic acyl (e.g. benzoyl (Bz),toluoyl, naphthoyl, fluorenylcarbonyl, etc.);

[0242] lower alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), etc.;

[0243] ar(lower)alkoxycarbonyl in which the aryl portion is optionallysubstituted with one or more suitable substituent(s) (e.g.benzyloxycarbonyl, bromobenzyloxycarbonyl, etc.);

[0244] lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonyl, etc.);

[0245] lower alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl,etc.);

[0246] ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropanoyl,phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl,naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl,naphthylisobutanoyl, naphthylpentanoyl, naphthylhexanoyl, etc.);

[0247] ar(lower)alkenoyl such as ar(C₃-C₆)alkenoyl (e.g.phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl,phenylhexenoyl, naphthylpropenoyl, naphthylbutenoyl,naphthylmethacryloyl, naphthylpentenoyl, naphthylhexenoyl, etc.), etc.];

[0248] lower alkenyl (e.g. vinyl, allyl, etc.); etc.

[0249] The preferable hydroxy protecting group for the present inventionis, for example, tetrahydropyranyl, trimethylsilyl,t-butyldimethylsilyl, etc.

[0250] The following abbreviations are also used in thepresent-specification: Boc (t-butyloxycarbonyl); HOBT or HOBt(1-hydroxybenzotriazole); WSCD(1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide); DMF(N,N-dimethylformamide); aq. (aqueous solution); Me (methyl); MeOH(methanol); Et (ethyl); EtOH (ethanol); tBu (t-butyl); TsCl(p-toluenesulfonyl chloride); Ac (acetyl); AcOH (acetic acid); AcOEt(ethyl acetate); AcONH₄ (ammonium acetate); Ph (phenyl); DIEA(diisopropylethylamine); THP (tetrahydropyranyl); THF (tetrahydrofuran)and TFA or TFAOH (trifluoroacetic acid).

[0251] Test Method

[0252] In order to show the usefulness of the compound [I] of theinvention, the pharmacological test result of the representativecompound of the present invention is shown in the following.

[0253] Test 1: Determination of Histone Deacetylase Inhibitor Activity

[0254] The partial purification of human histone deacetylase, thepreparation of [³H] acetyl histones, and the assay for histonedeacetylase activity were performed basically according to the method asproposed by Yoshida et al. as follows.

[0255] Partial Purification of Human Histone Deacetylase

[0256] The human histone deacetylase was partially purified from human Tcell leukemia Jurkat cells. Jurkat cells (5×10⁸ cells) were suspended in40 mL of the HDA buffer consisting of 15 mM potassium phosphate, pH 7.5,5% glycerol and 0.2 mM EDTA. After homogenization, nuclei were collectedby centrifugation (35,000×g, 10 min) and homogenized in 20 mL of thesame buffer supplemented with 1 M (NH₄)₂SO₄. The viscous homogenate wassonicated and clarified by centrifugation (35,000×g, 10 min), and thedeacetylase was precipitated by raising the concentration of (NH₄)₂SO₄to 3.5 M. The precipitated protein was dissolved in 10 mL of the HDAbuffer and dialyzed against 4 liters of the same buffer. The dialyzatewas then loaded onto a DEAE-cellulose (Whatman DE52) column (25×85 mm)equilibrated with the same buffer and eluted with 300 mL of a lineargradient (0-0.6 M) of NaCl. A single peak of histone deacetylaseactivity appeared between 0.3 and 0.4 M NaCl.

[0257] Preparation of [³H] Acetyl Histone

[0258] To obtain [³H] acetyl-labeled histone as the substrate for thehistone deacetylase assay, 1×10⁸ cells of Jurkat in 20 mL of RPMI-1640medium (supplemented with 10% FBS, penicillin (50 units/mL) andstreptomycin (50 μg/mL)) were incubated with 300 MBq [³H] sodium acetatein the presence of 5 mM sodium butyrate for 30 minutes in 5% CO₂-95% airatmosphere at 37° C. in a 75 cm² flask, harvested into a centrifuge tube(50 mL), collected by centrifugation at 1000 rpm for 10 minutes, andwashed once with phosphate-buffered saline. The washed cells weresuspended in 15 mL of ice-cold lysis buffer (10 mM Tris-HCl, 50 mMsodium bisulfite, 1% Triton X-100, 10 mM MgCl₂, 8.6% sucrose, pH 6.5).After Dounce homogenization (30 stroke), the nuclei were collected bycentrifugation at 1000 rpm for 10 minutes, washed 3 times with 15 mL ofthe lysis buffer, and once with 15 mL of ice-cooled washing buffer (10mM Tris-HCl, 13 mM EDTA, pH 7.4) successively. The pellet was suspendedin 6 mL of ice-cooled water using a mixer, and 68 μl of H₂SO₄ was addedto the suspension to give a concentration of 0.4 N. After incubation at4° C. for 1 hour, the suspension was centrifuged for 5 minutes at 15,000 rpm, and the supernatant was taken and mixed with 60 mL of acetone.After overnight incubation at −20° C., the coagulated material wascollected by microcentrifugation, air-dried, and stored at −80° C.

[0259] Assay for Histone Deacetylase Activity

[0260] For the standard assay, 10 μl of [³H] acetyl-labeled histoneswere added to 90 μl of the enzyme fraction, and the mixture wasincubated at 25° C. for 30 minutes. The reaction was stopped by additionof 10 μl of HCl. The released [³H] acetic acid was extracted with 1 mLof ethyl acetate, and 0.9 mL of the solvent layer was taken into 10 mLof toluene scintillation solution for determination of radioactivity.

[0261] Test 2: Determination of T-Cell Growth Inhibitor Activity

[0262] The T lymphocyte blastogenesis test was performed in microtiterplates with each well containing 1.5×10⁵ splenic cells of Lewis rats in0.1 mL RPMI-1640 medium supplemented with 10% fetal bovine serum-(FBS),50 mM 2-mercaptoethanol, penicilln (100 units/mL) and streptomycin (100μg/mL), to which Concanavalin A (1 μl/mL) was added. The cells wereincubated at 37° C. in a humidified atmosphere of 5% CO₂ for 72 hours.After the culture period, suppressive activities of the test compoundsin T lymphocyte blastogenesis were quantified by AlamarBlue (trademark)Assay. The test samples were dissolved in DMSO and further diluted withRPMI-1640 medium and added to the culture. The activities of the testcompounds were expressed as IC₅₀.

[0263] The results of those tests are shown in the Table 1. TABLE 1 HDACinhibitory activity and T-cell growth inhibitory activity of thecompound of the present invention Test 1: Test 2: HDAC T-cell growthinhibitory inhibitory activity activity Examples IC₅₀ (nM) IC₅₀ (nM)Compound E1 28 69 Compound E3 140 160 Compound E5 96 310 Compound E6 150150

[0264] The pharmaceutical composition of the present inventioncomprising histone deacetylase inhibitor such as the compound [I] isuseful as a therapeutic or prophylactic agent for diseases caused byabnormal gene expression, such as inflammatory disorders, diabetes,diabetic complications, homozygous thalassemia, fibrosis, cirrhosis,acute promyelocytic leukaemia (APL), protozoal infection, etc.Furthermore, it is useful as an antitumor agent or immunosuppressant,which prevents an organ transplant rejection and autoimmune diseases asexemplified below:

[0265] rejection reactions by transplantation of organs or tissues suchas the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas,small intestine, limb, muscle, nerve, intervertebral disc, trachea,myoblast, cartilage, etc.;

[0266] graft-versus-host reactions following bone marrowtransplantation;

[0267] autoimmune diseases such as rheumatoid arthritis, systemic lupuserythematosus, Hashimoto's thyroiditis, multiple sclerosis, myastheniagravis, type I diabetes, etc.; and infections caused by pathogenicmicroorganisms (e.g. Aspergillus fumigatus, Fusarium oxysporum,Trichophyton asteroides, etc.).

[0268] Furthermore, pharmaceutical preparations of the histonedeacetylase inhibitor, such as the compound [I], are useful for thetherapy or prophylaxis of the following diseases.

[0269] Inflammatory or hyperproliferative skin diseases or cutaneousmanifestations of immunologically-mediated diseases (e.g. psoriasis,atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheicdermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysisbullosa, urticaria, angioedema, vasculitides, erythema, dermaleosinophilia, lupus erythematosus, acne, alopecia greata, etc.);

[0270] autoimmune diseases of the eye (e.g. keratoconjunctivitis, vernalconjunctivitis, uveitis associated with Behcet's disease, keratitis,herpetic keratitis, conical keratitis, corneal epithelial dystrophy,keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave'sophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitissicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrineophthalmopathy, etc.);

[0271] reversible obstructive airways diseases [asthma (e.g. bronchialasthma, allergic asthma, intrinsic asthma, extrinsic asthma, dustasthma, etc.), particularly chronic or inveterate asthma (e.g. lateasthma, airway hyper-responsiveness, etc.), bronchitis, etc.];

[0272] mucosal or vascular inflammations (e.g. gastric ulcer, ischemicor thrombotic vascular injury, ischemic bowel diseases, enteritis,necrotizing enterocolitis, intestinal damages associated with thermalburns, leukotriene B4-mediated diseases, etc.); intestinalinflammations/allergies (e.g. coeliac diseases, proctitis, eosinophilicgastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis,etc.);

[0273] food-related allergic diseases with symptomatic manifestationremote from the gastrointestinal tract (e.g. migrain, rhinitis, eczema,etc.);

[0274] renal diseases (e.g. intestitial nephritis, Goodpasture'ssyndrome, hemolytic uremic syndrome, diabetic nephropathy, etc.);

[0275] nervous diseases (e.g. multiple myositis, Guillain-Barresyndrome, Meniere's disease, multiple neuritis, solitary neuritis,cerebral infarction, Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS), radiculopathy, etc.);

[0276] cerebral ischemic diseases (e.g., head injury, hemorrhage inbrain (e.g., subarachnoid hemorrhage, intracerebral hemorrhage, etc.),cerebral thrombosis, cerebral embolism, cardiac arrest, stroke,transient ischemic attack (TIA), hypertensive encephalopathy, etc.);

[0277] endocrine diseases (e.g. hyperthyroidism, Basedow's disease,etc.);

[0278] hematic diseases (e.g. pure red cell aplasia, aplastic anemia,hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmunehemolytic anemia, agranulocytosis, pernicious anemia, megaloblasticanemia, anerythroplasia, etc.);

[0279] bone diseases (e.g. osteoporosis, etc.);

[0280] respiratory diseases (e.g. sarcoidosis, pulmonary fibrosis,idiopathic interstitial pneumonia, etc.);

[0281] skin diseases (e.g. dermatomyositis, leukoderma vulgaris,ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, etc.);

[0282] circulatory diseases (e.g. arteriosclerosis, atherosclerosis,aortitis syndrome, polyarteritis nodosa, myocardosis, etc.);

[0283] collagen diseases (e.g. scleroderma, Wegener's granuloma,Sjögren's syndrome, etc.);

[0284] adiposis;

[0285] eosinophilic fasciitis;

[0286] periodontal diseases (e.g. damage to gingiva, periodontium,alveolar bone or substantia ossea dentis, etc.);

[0287] nephrotic syndrome (e.g. glomerulonephritis, etc.);

[0288] male pattern alopecia, alopecia senile;

[0289] muscular dystrophy;

[0290] pyoderma and Sezary syndrome;

[0291] chromosome abnormality-associated diseases (e.g. Down's syndrome,etc.);

[0292] Addison's disease;

[0293] active oxygen-mediated diseases {e.g. organ injury [e.g. ischemiccirculation disorders of organs (e.g. heart, liver, kidney, digestivetract, etc.) associated with preservation, transplantation, ischemicdiseases (e.g. thrombosis, cardial infarction, etc.), etc.];

[0294] intestinal diseases (e.g. endotoxin shock, pseudomembranouscolitis, drug- or radiation-induced colitis, etc.);

[0295] renal diseases (e.g. ischemic acute renal insufficiency, chronicrenal failure, etc.);

[0296] pulmonary diseases (e.g. toxicosis caused by pulmonary oxygen ordrugs (e.g. paracort, bleomycin, etc.), lung cancer, pulmonaryemphysema, etc.);

[0297] ocular diseases (e.g. cataracta, iron-storage disease (siderosisbulbi), retinitis, pigmentosa, senile plaques, vitreous scarring,corneal alkali burn, etc.);

[0298] dermatitis (e.g. erythema multiforme, linear immunoglobulin Abullous dermatitis, cement dermatitis, etc.); and

[0299] other diseases (e.g. gingivitis, periodontitis, sepsis,pancreatitis, diseases caused by environmental pollution (e.g. airpollution, etc.), aging, carcinogen, metastasis of carcinoma,hypobaropathy, etc.)};

[0300] diseases caused by histamine release or leukotriene C4 release;restenosis of coronary artery following angioplasty and prevention ofpostsurgical adhesions;

[0301] autoimmune diseases and inflammatory conditions (e.g., primarymucosal edema, autoimmune atrophic gastritis, premature menopause, malesterility, juvenile diabetes mellitus, pemphigus vulgaris, pemphigoid,sympathetic ophthalmitis, lens-induced uveitis, idiopathic leukopenia,active chronic hepatitis, idiopathic cirrhosis, discoid lupuserythematosus, autoimmune orchitis, arthritis (e.g. arthritis deformans,etc.), polychondritis, etc.);

[0302] Human Immunodeficiency Virus (HIV) infection, AIDS; allergicconjunctivitis;

[0303] hypertrophic cicatrix, keloid due to trauma, burn or surgery,etc.

[0304] Therefore, the pharmaceutical composition of the presentinvention is useful for the therapy and prophylaxis of liver diseases[e.g. immunogenic diseases (e.g. chronic autoimmune liver diseases suchas autoimmune hepatic diseases, primary biliary cirrhosis, sclerosingcholangitis, etc.), partial liver resection, acute liver necrosis (e.g.necrosis caused by toxins, viral hepatitis, shock, anoxia, etc.),hepatitis B, non-A non-B hepatitis, hepatocirrhosis, hepatic failure(e.g. fulminant hepatitis, late-onset hepatitis, “acute-on-chronic”liver failure (acute liver failure on chronic liver diseases, etc.),etc.), etc.].

[0305] The pharmaceutical composition of the present invention can beused in the form of pharmaceutical preparation, for example, in a solid,semisolid or liquid form, which contains the histone deacetylaseinhibitor, such as the compound [I], as an active ingredient inadmixture with an organic or inorganic carrier or excipient suitable forexternal, enteral or parenteral administrations. The active ingredientmay be compounded, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, injections, ointments,liniments, eye drops, lotion, gel, cream, and any other form suitablefor use.

[0306] The carriers those can be used for the present invention includewater, glucose, lactose, gum acacia, gelatin, mannitol, starch paste,magnesium trisilicate, talc, corn starch, keratin, colloidal silica,potato starch, urea and other carriers suitable for use in manufacturingpreparations in a solid, semisolid, or liquid form. Furthermore,auxiliary, stabilizing, thickening, solubilizing and coloring agents andperfumes may be used.

[0307] For applying the composition to human, it is preferable to applyit by intravenous, intramuscular, topical or oral administration, or bya vascular stent impregnated with the compound [I]. While the dosage oftherapeutically effective amount of the histone deacetylase inhibitor,such as the compound [I], varies from and also depends upon the age andcondition of each individual patient to be treated, when an individualpatient is to be treated, in the case of intravenous administration, adaily dose of 0.01-10 mg of the histone deacetylase inhibitor, such asthe compound [I], per kg weight of human being, in the case ofintramuscular administration, a daily dose of 0.1-10 mg of the histonedeacetylase inhibitor, such as the compound of the formula [I], per kgweight of human being, and in the case of oral administration, a dailydose of 0.5-50 mg of the histone deacetylase inhibitor, such as thecompound [I], per kg weight of human being, is generally given fortreatment.

[0308] During the preparation of the above-mentioned pharmaceuticaladministration forms, the compound [I] or a salt thereof can also becombined together with other immunosuppressive substances, for examplerepamycin, mycophenolic acid, cyclosporin A, tacrolimus or brequinarsodium.

[0309] Hereinafter the reactions in each Preparations and Examples forpreparing the compound [I] of the present invention are explained inmore detail. The invention should not be restricted by the followingPreparations and Examples in any way.

[0310] Preparation 1

[0311] To a solution of 4-iodophenylacetic acid (1346 mg) inN,N-dimethylformamide (15 mL) was added tert-butyl2-aminophenylcarbamate (1.07 g), 1-hydroxybenzotriazole (HOBT) (764 mg),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g),and the mixture was stirred at ambient temperature for 3 hours. Themixture was poured into water and extracted with ethyl acetate. Theorganic phase was sequentially washed with saturated aqueous ammoniumchloride solution, saturated aqueous sodium hydrogen carbonate solutionand brine. The organic phase was dried over magnesium sulfate andevaporated in vacuo. The residue was purified by silica gelchromatography eluting with a mixture of hexane and ethyl acetate (4:1to 2:1) to give Compound (1) as a pale yellow amorphous (2.03 g).

[0312]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.50 (3×3H, s), 3.66 (2H, s), 6.62(1H, brs), 7.07-7.20 (4H, m), 7.33 (1H, m), 7.47 (1H, m), 7.69 (2×1H, d,J=8.3 Hz), 8.00 (1H, brs);

[0313] MASS (ES+): m/e 453.

[0314] Preparation 2

[0315] To a stirred solution of Compound (1) (25.6 g) in ethanol (300mL) was added concentrated hydrochloric acid (30 mL), and the mixturewas refluxed for 1 hour. The solvent was evaporated in vacuoazeotropically with toluene. The residual solid was collected with themixture of ethanol and ethyl acetate (1:10) to give Compound (2) as anorange solid (20.0 g).

[0316]¹H-NMR (300 MHz, CDCl₃, δ): 4.52 (2H, s), 7.30 (2×1H, d, J=8.3Hz), 7.49-7.57 (2H, m), 7.73-7.82 (4H, m);

[0317] MASS (ES+): m/e 335.

[0318] Preparation 3

[0319] To a stirred solution of Compound (2) (114 mg) in dioxane (3 mL)and 1N-sodium hydroxide (0.8 mL) was added p-toluenesulfonyl chloride(70 mg) at 0° C. The mixture was allowed to warm to ambient temperatureand stirred for 30 minutes. Additional p-toluenesulfonyl chloride (70mg) was added, then 1N-sodium hydroxide (0.5 mL) was added so that thefinal pH was 9. The mixture was stirred at ambient temperature for 2hours. The solvent was evaporated in vacuo and the resulting solutionwas extracted with ethyl acetate. The organic phase was washed withbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by preparative thin layer chromatography (hexane:ethylacetate=2:1) to give Compound (3) as a pale yellow amorphous (130 mg).

[0320]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.35 (3H, s), 4.56 (2H, s), 7.05(2×1H, d, J=8.5 Hz), 7.32-7.44 (4H, m), 7.63-7.70 (3H, m), 7.78 (2×1H,d, J=8.5 Hz), 7.94 (1H, d, J=6.5 Hz);

[0321] MASS (ES+): m/e 489.

[0322] Preparation 4

[0323] To a stirred solution of Compound (3) (1,137 mg) inN,N-dimethylformamide (15 mL) was added acrylic acid (0.8 mL),palladium(II) acetate (26 mg), tris(2-methylphenyl)phosphine (142 mg)and N,N-diisopropylethylamine (1.25 ml). The mixture was stirred at 120°C. for 90 minutes. The resulting mixture was allowed to cool to ambienttemperature, poured into water and extracted with ethyl acetate. Theorganic phase was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica columnchromatography eluting with a mixture of chloroform and methanol (20:1)to give Compound (4) as a pale yellow amorphous (455 mg).

[0324]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.32 (3H, s), 4.63 (2H, s), 6.51(1H, d, J=16 Hz), 7.26-7.44 (6H, m), 7.54-7.69 (4H, m), 7.79 (2×1H, d,J=8.4 Hz), 7.94 (1H, m);

[0325] MASS (ES+): m/e 433.

[0326] Preparation 5

[0327] To a stirred solution of Compound (4) (70 mg) inN,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (HOBT) (26mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (37mg) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (23 mg), and theresulting mixture was stirred at ambient temperature for 14 hours. Tothe reaction mixture were added additional 1-hydroxybenzotriazole (13mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (19mg) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (12 mg), and themixture was stirred for 6 hours. The reaction mixture were diluted withethyl acetate and washed succesively with water, saturated ammoniumchloride solution, saturated sodium hydrogen carbonate solution andbrine. The organic phase was dried over magnesium sulfate andconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography (chloroform:methanol=10:1) to give Compound (5) asa white amorphous (503 mg). The Compound (5) was used in Example 1.

[0328]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.44-1.76 (6H, m), 3.52 (1H, m),3.95 (1H, m), 4.19 (1H, m), 4.90 (1H, m), 6.47 (1H, d, J=15.8 Hz),7.09-7.19 (2H, m), 7.34-7.58 (7H, m), 11.23 (1H, s), 12.30 (1H, s);

[0329] MASS (ES+): m/e 378.

[0330] Preparation 6

[0331] To a stirred solution of (4-bromophenyl)acetic acid (80.0 g, 372mmol) in N,N-dimethylformamide (640 mL) was added acrylic acid t-butylester (95.4 g), palladium(II) acetate (1.67 g), triphenylphosphine (3.91g) and N,N-diisopropylethylamine (162 mL). The mixture was stirred at100° C. for 7 hours. The resulting mixture was allowed to cool toambient temperature, poured into 1N-hydrochloric acid and extracted withethyl acetate twice. The combined organic phase was extracted withsaturated sodium hydrogen carbonate solution three times. The combinedaqueous phase was acidified with concentrated hydrogen chloride to pH 2and extracted with ethyl acetate. The organic phase was washed withbrine, dried over magnesium sulfate and concentrated in vacuo to giveCompound (6) as a pale yellow solid (78.1 g).

[0332]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 3.67 (2H, s), 6.35 (1H,d, J=16 Hz), 7.29 (2H, d, J=8 Hz), 7.47 (2H, d, J=8 Hz), 7.56 (1H, d,J=16 Hz).

[0333] Preparation 7

[0334] To a solution of Compound (6) (77.7 g), tert-butyl2-aminophenylcarbamate (61.7 g) and 1-hydroxybenzotriazole (HOBT) (44.0g) in N,N-dimethylformamide (777 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (62.5 g) at4° C. The mixture was warmed to ambient temperature and stirred for 2hours. The reaction mixture was added saturated aqueous sodiumhydrogencarbonate (777 mL) and water (3.1 L), and extracted with ethylacetate (1.5 L). The organic layer was washed with 5% aqueous potassiumhydrogen sulfate (500 mL), saturated aqueous sodium hydrogencarbonate(500 mL) and brine (500 mL), dried over magnesium sulfate, filtered andevaporated in vacuo to give Compound (7) (135 g).

[0335]¹H-NMR (300 MHz, CDCl₃, δ): 1.49 (9H, s), 1.54 (9H, s), 3.74 (2H,s), 6.36 (1H, d, J=16 Hz), 6.66 (1H, brs), 7.10-7.20 (2H, m), 7.33-7.40(3H, m), 7.44-7.54 (3H, m), 7.57 (1H, d, J=16 Hz), 7.98 (1H, brs).

[0336] Preparation 8

[0337] A solution of Compound (7) (47.6 g) in 1N-hydrogen chloride inacetic acid (60 mL) was heated at 120° C. for 1 hour. The resultingmixture was allowed to cool to ambient temperature and diluted withethyl acetate. The resulted precipitate was filtered and the residue waswashed with ethyl acetate to give Compound (8) (28.9 g).

[0338]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.56 (2H, s), 6.56 (1H, d, J=16 Hz)7.48-7.55 (4H, m), 7.59 (1H, d, J=16 Hz), 7.72-7.80 (4H, m).

[0339] Preparation 9

[0340] To a solution of Compound (8) (50.0 g),O-tetrahydro-2H-pyran-2-ylhydroxylamine (29.8 g) and1-hydroxybenzotriazole (34.3 g) in N,N-dimethylformamide (795 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (39.5 g) at 9° C.The mixture was warmed to ambient temperature and stirred for 2 hours.The reaction mixture was added saturated aqueous sodiumhydrogencarbonate (795 mL) and water (3.2 L). The resulting precipitatewas collected by filtation, and washed with saturated aqueous sodiumhydrogencarbonate (250×2 mL) and water (250×2 mL) to give Compound (9)(57.2 g).

[0341]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48-1.75 (6H, m), 3.48-3.57 (1H,m), 3.89-4.00 (1H, m), 4.20 (2H, s), 4.90 (1H, brs), 6.47 (1H, d, J=16Hz), 7.07-7.16 (2H, m), 7.34-7.57 (7H, m), 11.2 (1H, brs), 12.3 (1H,brs).

[0342] Preparation 10

[0343] To a stirred solution of 2-(4-iodobenzyl)-1H-benzimidazole (451mg) in dimethylformamide (5 ml) was added portionwise sodium hydride (81mg, 60% oil dispersion) at 0° C. After 30 minutes, benzyl bromide (0.19mL) was added dropwise to the mixture, and the mixture was stirred for30 minutes. The resulting mixture was poured into saturated ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas washed with brine, dried over sodium sulfate, and concentrated invacuo. The residue was purified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (10) as a pale yellow oil(225 mg). In this preparation, a by-product(1-benzyl-2-[1-(4-iodophenyl)-2-phenylethyl]-1H-benzimidazole) (306 mg)was also obtained and was used in Preparation 23 described below.

[0344]¹H-NMR (300 MHz, CDCl₃, δ): 4.18 (2H, s), 5.19 (2H, s), 6.86-6.97(4H, m), 7.19-7.32 (6H, m), 7.56 (2×1H, J=8.5 Hz), 7.81 (1H, d, J=7.5Hz);

[0345] MASS (ES+): m/e 425.

[0346] Preparation 11

[0347] Compound (11) was obtained from Compound (10) according to amanner similar to Preparation 4 as a pale yellow oil (142 mg).

[0348]¹H-NMR (300 MHz, CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 4.26 (2H, s),4.26 (2H, q, J=7 Hz), 5.21 (2H, s), 6.38 (1H, d, J=16 Hz), 6.88-6.96(2H, m), 7.18-7.32 (8H, m), 7.41 (2×1H, d, J=8 Hz), 7.62 (1H, d, J=16Hz), 7.81 (1H, d, J=8 Hz);

[0349] MASS (ES+): m/e 397.

[0350] Preparation 12

[0351] To a stirred solution of Compound (11) (140 mg) in methanol (6mL) was added 1N sodium hydroxide solution (0.71 mL). The mixture wasstirred at ambient temperature for 7 hours. The solvent was evaporatedin vacuo, and the residue was dissolved in water and washed with diethylether. The aqueous phase was acidified to pH 3 with hydrochloric acid,and extracted three times with ethyl acetate. The combined organic phasewas washed with brine, dried over sodium sulfate and evaporated in vacuoto give Compound (12) as a pale yellow powder (111 mg).

[0352]¹H-NMR (300 MHz, CDCl₃, δ): 4.29 (2H, s), 5.23 (2H, s), 6.36 (1H,d, J=15.7 Hz), 6.88-6.96 (2H, m), 7.16-7.34 (8H, m), 7.41 (2×1H, d, J=8Hz), 7.62 (1H, d, J=15.7 Hz), 7.81 (1H, d, J=7.5 Hz);

[0353] MASS (ES+): m/e 368.

[0354] Preparation 13

[0355] Compound (13) was obtained from Compound (12) according to amanner similar to Preparation 9 as a white amorphous (111 mg).

[0356]¹H-NMR (300 MHz, CDCl₃, δ): 1.52-1.95 (6H, m), 3.61 (1H, m), 3.94(1H, m), 4.25 (2H, s), 5.02 (1H, m), 5.20 (2H, s), 6.88-6.96 (2H, m),7.12-7.41 (11H, m), 7.66 (1H, d, J=15.5 Hz), 7.82 (1H, d, J=8 Hz);

[0357] MASS (ES+): m/e 468.

[0358] Preparation 14

[0359] To a stirred solution of 3-phenylpropanoic acid (7.51 g) inacetic acid (70 mL) were added periodic acid (2.39 g), iodine (5.08 g),concentrated sulfuric acid (1.5 mL) and water (10 mL), and the mixturewas stirred at 70° C. for 7 hours. The solvent was evaporated in vacuo,and the residue was diluted with water and extracted with ethyl acetate.The organic phase was washed with 10% sodium thiosulfate solution twice,then washed with brine, dried over magnesium sulfate and evaporated invacuo. The precipitate was crystallized from ethyl acetate and hexane togive Compound (14) (5.80 g).

[0360]¹H-NMR (300 MHz, CDCl₃, δ): 2.66 (2H, t, J=7 Hz), 2.90 (2H, t, J=7Hz), 6.97 (2×1H, d, J=8.5 Hz), 7.61 (2×1H, d, J=8.5 Hz);

[0361] MASS (ES−): m/e 275.

[0362] Preparation 15

[0363] Compound (15) was obtained from Compound (14) according to amanner similar to Preparation 1 (9.50 g).

[0364]¹H-NMR (300 MHz, CDCl₃, δ): 1.51 (3×3H, s), 2.64 (2H, t, J=7.5Hz), 3.00 (2H, t, J=7.5 Hz), 6.69 (1H, s), 7.00 (2×1H, d, J=8.5 Hz),7.12-7.20 (2H, m), 7.33 (1H, m), 7.45 (1H, m), 7.62 (2×1H, d, J=8.5 Hz),7.97 (1H, brs);

[0365] MASS (ES+): m/e 467.

[0366] Preparation 16

[0367] Compound (16) was obtained from Compound (15) according to amanner similar to Preparation 2 (1.55 g).

[0368]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.20 (2H, t, J=7.5 Hz), 3.41 (2H, t,J=7.5 Hz), 7.10 (2×1H, d, J=8.5 Hz), 7.48-7.56 (2H, m), 7.66 (2×1H, d,J=8.5 Hz), 7.74-7.82 (2H, m);

[0369] MASS (ES+): m/e 349.

[0370] Preparation 17

[0371] Compound (17) was obtained from Compound (16) according to amanner similar to Preparation 3 (7.10 g).

[0372]¹H-NMR (300 MHz, CDCl₃, δ): 2.38 (3H, s), 3.18 (2H, t, J=7 Hz),3.43 (2H, t, J=7 Hz), 7.05 (2×1H, d, J=8.5 Hz), 7.25 (2×1H, d, J=8.5Hz), 7.30-7.40 (2H, m), 7.61 (2×1H, d, J=8.5 Hz), 7.67 (1H, m), 7.71(2×1H, d, J=8.5 Hz), 8.03 (1H, m);

[0373] MASS (ES+): m/e 503.

[0374] Preparation 18

[0375] Compound (18) was obtained from Compound (17) according to amanner similar to Preparation 4 (3.59 g).

[0376]¹H-NMR (300 MHz, CDCl₃, δ): 2.38 (3H, s), 3.27 (2H, t, J=7 Hz),3.47 (2H, t, J=7 Hz), 6.44 (1H, d, J=16 Hz), 7.25 (2×1H, d, J=8 Hz),7.31-7.40 (4H, m), 7.50 (2×1H, d, J=8 Hz), 7.66-7.81 (4H, m), 8.04 (1H,m);

[0377] MASS (ES+): m/e 447.

[0378] Preparation 19

[0379] Compound (19) was obtained from Compound (18) according to amanner similar to Preparation 5 (2.20 g). The Compound (19) was used inExample 3.

[0380]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.76 (6H, m), 3.08-3.18 (4H,m), 3.53 (1H, m), 3.95 (1H, m), 4.90 (1H, m), 6.45 (1H, d, J=15.5 Hz),7.08-7.16 (2H, m), 7.31 (2×1H, d, J=8 Hz), 7.40-7.54 (5H, m), 11.21 (1H,s), 12.28 (1H, br);

[0381] MASS (ES+): m/e 392.

[0382] Preparation 20

[0383] To a stirred solution of 1H-benzimidazole (500 mg) inN,N-dimethylformamide (10 mL) was added sodium hydride (186 mg, 60% ofoil suspension) at 0° C. After 90 minutes, 4-iodobenzyl bromide wasadded to the mixture and the mixture was stirred at ambient temperaturefor 1 hour. The reaction mixture was quenched with saturated ammoniumchloride solution, diluted with water and extracted with ethyl acetate.The organic phase was washed with brine, dried over sodium sulfate andconcentrated in vacuo. The residue was triturated with hexane to giveCompound (20) as a white solid. (1.20 g).

[0384]¹H-NMR (300 MHz, CDCl₃, δ): 5.31 (2H, s), 6.92 (2×1H, d, J=8.5Hz), 7.21-7.33 (3H, m), 7.67 (2×1H, d, J=8.5 Hz), 7.84 (1H, m), 7.95(1H, s);

[0385] MASS (ES+): m/e 335.

[0386] Preparation 21

[0387] Compound (21) was obtained from Compound (20) according to amanner similar to Preparation 4 (614 mg).

[0388]¹H-NMR (300 MHz, DMSO-d, 6): 5.53 (2H, s), 6.50 (1H, d, J=16 Hz),7.15-7.24 (2H, m), 7.32 (2×1H, d, J=8.5 Hz), 7.51 (1H, m), 7.52 (1H, d,J=16 Hz), 7.61-7.70 (3H, m), 8.43 (1H, s);

[0389] MASS (ES+): m/e 279.

[0390] Preparation 22

[0391] Compound (22) was obtained from Compound (21) according to amanner similar to Preparation 5 (536 mg). The obtained Compound (22) wasused in Example 4.

[0392]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.76 (6H, m), 3.52 (1H, m),3.94 (1H, m), 4.89 (1H, m), 5.53 (2H, s), 6.46 (1H, d, J=16 Hz),7.16-7.25 (2H, m), 7.33 (2×1H, d, J=8.5 Hz), 7.44 (1H, d, J=16 Hz), 7.51(1H, m), 7.54 (2×1H, d, J=8.5 Hz), 7.67 (1H, m), 8.42 (1H, s), 11.24(1H, s);

[0393] MASS (ES+): m/e 378.

[0394] Preparation 23

[0395] Compound (23) was obtained from the by-product obtained inPreparation 10 according to a manner similar to Preparation 4 (150 mg).

[0396]¹H-NMR (300 MHz, CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 3.35 (1H, dd,J=13.5, 7.5 Hz), 3.85 (1H, dd, J=13.5, 7.5 Hz), 4.25 (2H, q, J=7 Hz),4.28 (1H, dd, J=7.5, 7.5 Hz), 5.05 (1H, d, J=16.5 Hz), 5.11 (1H, d,J=16.5 Hz), 6.35 (1H, d-, J=16 Hz), 6.75 (2×1H, dd, J=7.5, 1 Hz),6.93-7.00 (2H, m), 7.09-7.38 (13H, m), 7.59 (1H, d, J=16 Hz), 7.91 (1H,d, J=8 Hz);

[0397] MASS (ES+): m/e 487.

[0398] Preparation 24

[0399] Compound (24) was obtained from Compound (23) according to amanner similar to Preparation 12 (135 mg).

[0400]¹H-NMR (300 MHz, CDCl₃, δ): 3.37 (1H, dd, J=13.5, 7.5 Hz), 3.86(1H, dd, J=13.5, 7.5 Hz), 4.31 (1H, dd, J=7.5, 7.5 Hz), 5.06 (1H, d,J=15.7 Hz), 5.11 (1H, d, J=15.7 Hz), 6.39 (1H, d, J=15.7 Hz), 6.74(2×1H, d, J=7 Hz), 6.93-7.02 (2H, m), 7.08-7.33 (11H, m), 7.36 (2×1H, d,J=8 Hz), 7.68 (1H, d, J=15.7 Hz), 7.94 (2×1H, d, J=7.5 Hz);

[0401] MASS (ES+): m/e 459.

[0402] Preparation 25

[0403] Compound (25) was obtained from Compound (24) according to amanner similar to Preparation 9 (140 mg). The obtained Compound (25) wasused in Example 5.

[0404]¹H-NMR (300 MHz, CDCl₃, δ): 1.55-1.92 (6H, m), 3.35 (1H, dd,J=13.5, 7.5 Hz), 3.64 (1H, m), 3.84 (1H, dd, J=13.5, 7.5 Hz), 3.95 (1H,m), 4.28 (1H, dd, J=7.5, 7.5 Hz), 5.00 (1H, m), 5.04 (1H, d, J=17 Hz),5.11 (1H, d, J=17 Hz), 6.75 (2×1H, d, J=7 Hz), 6.92-7.00 (2H, m),7.08-7.37 (14H, m), 7.64 (1H, d, J=15 Hz), 7.90 (1H, d, J=8 Hz);

[0405] MASS (ES+): m/e 558.

[0406] Preparation 26

[0407] Compound (26) was obtained from (3-bromophenyl)acetic acidaccording to a manner similar to Preparation 6 (6.20 g).

[0408]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (3×3H, s), 306 (2H, s), 6.37 (1H,d, J=15.8 Hz), 7.25-7.46 (4H, m), 7.56 (1H, d, J=15.8 Hz);

[0409] MASS (ES−): m/e 261.

[0410] Preparation 27

[0411] Compound (27) was obtained from Compound (26) according to amanner similar to Preparation 7 (6.96 g).

[0412]¹H-NMR (300 MHz, CDCl₃, δ): 1.48 (3×3H, s), 1.53 (3×3H, s), 3.74(2H, s), 6.39 (1H, d, J=15.8 Hz), 6.70 (1H, brs), 7.09-7.20 (2H, m),7.32-7.52 (6H, m), 7.56 (1H, d, J=15.8 Hz), 8.04 (1H, brs):

[0413] MASS (ES+): m/e 453.

[0414] Preparation 28

[0415] Compound (28) was obtained from Compound (27) according to amanner similar to Preparation 8 (4.19 g).

[0416]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.58 (1H, d, J=16 Hz),7.42-7.58 (5H, m), 7.58 (1H, d, J=16 Hz), 7.66 (1H, m), 7.74-7.82 (2H,m), 7.87 (1H, brs);

[0417] MASS (ES+): m/e 279.

[0418] Preparation 29

[0419] Compound (29) was obtained from Compound (28) according to amanner similar to Preparation 9 (3.34 g). The obtained Compound (29) wasused in Example 6.

[0420]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.44-1.76 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.20 (2H, s), 4.90 (1H, m), 6.50 (1H, d, J=16 Hz),7.08-7.16 (2H, m), 7.32-7.60 (7H, m), 11.25 (1H, s), 12.31 (1H, brs);

[0421] MASS (ES+): m/e 378.

[0422] Preparation 30

[0423] Compound (30) was obtained from{4-[(1E)-3-tert-butoxy-3-oxo-1-propenyl]phenyl}acetic acid according toa manner similar to Preparation 1 (324 mg).

[0424]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (3×3H, s), 3.176 (1H, s), 3.723(1H, s), 5.00 (1H, s), 5.01 (1H, s), 6.51 (1H, d, J=15.7 Hz), 6.82 (1H,m), 7.19-7.60 (10H, m), 7.66 (2×1H, d, J=8 Hz), 9.45 (0.5H, s), 9.47(0.5H, s);

[0425] MASS (ES+): m/e 429.

[0426] Preparation 31

[0427] Compound (31) was obtained from Compound (30) according to amanner similar to Preparation 8 (216 mg).

[0428]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.59 (2H, s), 6.57 (1H, d, J=16 Hz)7.42 (1H, m), 7.51 (2×1H, d, J=7.5 Hz), 7.53 (2×1H, d, J=8.5 Hz), 7.60(1H, d, J=16 Hz), 7.69-7.88 (6H, m), 7.96 (1H, s);

[0429] MASS (ES+): m/e 355.

[0430] Preparation 32

[0431] Compound (32) was obtained from Compound (31) according to amanner similar to Preparation 9 (231 mg). The obtained Compound (32) wasused in Example 7.

[0432]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.78 (6H, m), 3.52 (1H, m),3.95 (1H, m), 4.22 (2H, s), 4.90 (1H, m), 6.48 (1H, d, J=15 Hz),7.30-7.81 (13H, m), 11.23 (1H, s), 12.38 (1/2H, s), 12.41 (1/2H, s);

[0433] MASS (ES+): m/e 454.

[0434] Preparation 33

[0435] Compound (33) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (5.48 g).

[0436]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.50 (2H, s), 6.55 (1H, d, J=16 Hz),7.47 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.56-7.75 (4H, m), 7.97(1H, s).

[0437] MASS (ESI): m/z 357 (M+1).

[0438] Preparation 34

[0439] Compound (34) was obtained from Compound (33) according to amanner similar to Preparation 9 (557 mg). The Compound (34) was used inExample 8.

[0440]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48-1.74 (6H, m), 3.48-3.57 (1H,m), 3.89-4.00 (1H, m), 4.20 (2H, s), 4.90 (1H, brs), 6.47 (1H, d, J=16Hz), 7.26 (1H, dd, J=2, 8 Hz), 7.34-7.56 (6H, m), 7.68 (1H, brs).

[0441] MASS (ESI): m/z 456 (M+1).

[0442] Preparation 35

[0443] To a mixture of Compound (34) (200 mg), 4-acetylphenylboronicacid (167 mg) and dichlorobis(triphenylphosphine)palladium(II) (10.7 mg)in dioxane (10 mL) was added 0.2M sodium carbonate (2.5 mL), and themixture was heated at 90° C. for 5 hours. After cooling, the reactionmixture was partitioned between ethyl acetate and water. The inorganiclayer was separated and acidified with 1N hydrochloric acid. Theresulting precipitate was collected by filtration, and washed with waterand ethyl acetate to give Compound (35) (193 mg). The Compound (35) wasused in Example 9.

[0444]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.63 (3H, s), 4.57 (2H, s), 6.56(1H, d, J=16 Hz), 7.52 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.74 (2H,d, J=8 Hz), 7.85-7.92 (4H, m), 8.03-8.10 (3H, m);

[0445] MASS (ESI): m/z 397 (M+1).

[0446] Preparation 36

[0447] Compound (36) was obtained from Compound (34) according to amanner similar to Preparation 35 (163 mg). The Compound (36) was used inExample 10.

[0448]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.37 (2H, s), 6.53 (1H, d, J=16 Hz),7.12-7.16 (1H, m), 7.45-7.71 (9H, m), 7.81 (1H, s);

[0449] MASS (ESI): m/z 361 (M+1).

[0450] Preparation 37

[0451] Compound (37) was obtained from Compound (34) according to amanner similar to Preparation 35 (183 mg). The Compound (37) was used inExample 11.

[0452]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.55 (2H, s), 6.56 (1H, d, J=16 Hz),7.40-8.01 (11H, m);

[0453] MASS (ESI): m/z 361 (M+1).

[0454] Preparation 38

[0455] Compound (38) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (2.07 g).

[0456]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.47 (2H, s), 6.54 (1H, d, J=16 Hz),7.46 (2H, d, J=8 Hz), 7.58 (1H, d, J=16 Hz), 7.70 (2H, d, J=8 Hz), 7.77(1H, d, J=8 Hz), 7.83 (1H, d, J=8 Hz), 8.26 (1H, s);

[0457] MASS (ESI): m/z 304 (M+1).

[0458] Preparation 39

[0459] Compound (39) was obtained from Compound (38) according to amanner similar to Preparation 9 (2.14 g). The Compound (39) was used inExamples 12 and 18.

[0460]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.49-1.72 (6H, m), 3.50-3.56 (1H,m), 3.91-3.99 (1H, m), 4.26 (2H, s), 4.91 (1H, brs), 6.47 (1H, d, J=16Hz), 7.37 (2H, d, J=8 Hz), 7.46 (1H, d, J=16 Hz), 7.51-7.57 (3H, m),7.65 (1H, d, J=8 Hz), 8.32 (1H, brs);

[0461] MASS (ESI): m/z 401 (M−1).

[0462] Preparation 40

[0463] Compound (40) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (955 mg). The Compound (40) was used inExample 13.

[0464]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.50 (2H, s), 6.55 (1H, d, J=16 Hz),7.32-7.39 (1H, m), 7.47 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.62(1H, dd, J=2, 8 Hz), 7.72 (2H, d, J=8 Hz), 7.74-7.79 (1H, m);

[0465] MASS (ESI): m/z 297 (M+1).

[0466] Preparation 41

[0467] Compound (41) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (1.02 g).

[0468]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.52 (2H, s), 6.55 (1H, d, J=16 Hz),7.48 (2H, d, J=8 Hz), 7.50 (1H, dd, J=2, 8 Hz), 7.59 (1H, d, J=16 Hz),7.72 (2H, d, J=8 Hz), 7.75 (1H, d, J=8 Hz), 7.85 (1H, J=2 Hz);

[0469] MASS (ESI): m/z 313 (M+1).

[0470] Preparation 42

[0471] Compound (42) was obtained from Compound (41) according to amanner similar to Preparation 9 (839 mg). The Compound (42) was used inExample 14.

[0472]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.49-1.71 (6H, m), 3.49-3.57 (1H,m), 3.88-4.02 (1H, m), 4.20 (2H, s), 4.88-4.93 (1H, m), 6.43-6.52 (1H,m), 7.12-7.18 (1H, m), 7.36 (2H, d, J=8 Hz), 7.46 (1H, d, J=16 Hz), 7.53(2H, d, J=8 Hz), 7.53-7.60 (1H, m), 7.64 (1H, d, J=8 Hz);

[0473] MASS (ESI): m/z 412 (M+1).

[0474] Preparation 43

[0475] Compound (43) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (411 mg).

[0476]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.78-2.84 (4H, m), 3.13-3.20 (4H,m), 4.54 (2H, s), 6.55 (1H, d, J=16 Hz), 7.16-7.76 (8H, m);

[0477] MASS (ESI): m/z 377 (M+1).

[0478] Preparation 44

[0479] Compound (44) was obtained from Compound (43) according to amanner similar to Preparation 9 (23 mg). The Compound (44) was used inExample 15.

[0480]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54-1.87 (6H, m), 2.36 (3H, s),2.58-2.64 (4H, m), 3.12-3.20 (4H, m), 3.58-3.66 (1H, m), 3.92-4.04 (1H,m), 4.15 (2H, s), 5.02-5.10 (1H, m), 6.92-7.60 (9H, m);

[0481] MASS (ESI): m/z 476 (M+1).

[0482] Preparation 45

[0483] Compound (45) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (358 mg).

[0484]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.16-3.22 (4H, m), 3.76-3.83 (4H,m), 4.53 (2H, s), 6.56 (1H, d, J=16 Hz), 7.34-7.76 (8H, m);

[0485] MASS (ESI): m/z 364 (M+1).

[0486] Preparation 46

[0487] Compound (46) was obtained from Compound (45) according to amanner similar to Preparation 9 (59 mg). The Compound (46) was used inExample 16.

[0488]¹H-NMR (300 MHz, CDCl₃, δ): 1.51-1.87 (6H, m), 3.05-3.13 (4H, m),3.57-3.64 (1H, m), 3.83-3.91 (4H, m), 3.95-4.04 (1H, m), 4.15 (2H, s),5.04-5.13 (1H, m), 6.91-7.61 (9H, m);

[0489] MASS (ESI): m/z 463 (M+1).

[0490] Preparation 47

[0491] Compound (47) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (517 mg).

[0492]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.57-1.69 (2H, m), 1.83-1.94 (4H,m), 3.37-3.50 (4H, m), 4.52 (2H, s), 6.48-6.58 (1H, m), 7.40-7.74 (8H,m);

[0493] MASS (ESI): m/z 362 (M+1).

[0494] Preparation 48

[0495] Compound (48) was obtained from Compound (47) according to amanner similar to Preparation 9 (47 mg). The Compound (48) was used inExample 17.

[0496]¹H-NMR (300 MHz, CDCl₃, δ): 1.50-1.87 (12H, m), 3.05-3.11 (4H, m),3.57-3.66 (1H, m), 3.94-4.05 (1H, m), 4.14 (2H, s), 5.02-5.12 (1H, m),6.94-7.48 (9H, m);

[0497] MASS (ESI): m/z 461 (M+1).

[0498] Preparation 49

[0499] Compound (49) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (1.17 g).

[0500]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.90 (3H, s), 4.49 (2H, s), 6.54(1H, d, J=16 Hz), 7.47 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.72 (2H,d, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.00 (1H, dd, J=2, 8 Hz), 8.24 (1H,brs);

[0501] MASS (ESI): m/z 337 (M+1).

[0502] Preparation 50

[0503] Compound (50) was obtained from Compound (49) according to amanner similar to Preparation 9 (1.30 g). The Compound (50) was used inExample 19.

[0504]¹H-NMR (300 MHz, DMSO-d, 6): 1.48-1.74 (6H, m), 3.48-3.58 (1H, m),3.85 (3H, s), 3.87-4.00 (1H, m), 4.25 (2H, brs), 4.90 (1H, brs), 6.47(1H, d, J=16 Hz), 7.35-7.65 (6H, m), 7.74-8.16 (2H, m);

[0505] MASS (ESI): m/z 436 (M+1).

[0506] Preparation 51

[0507] To a solution of Compound (50) (299 mg) in dioxane (7 mL) wasadded 1N sodium hydroxide (2.1 mL). After stirring at 80° C. for 1 hour,the reaction mixture was added water (25 mL) and acidified with 1Nhydrochloric acid (to pH 3-4). A resulting precipitate was collected byfiltration and washed with water to give Compound (51) (255 mg). TheCompound (51) was used in Example 20.

[0508]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.49-1.74 (6H, m), 3.47-3.59 (1H,m), 3.87-4.01 (1H, m), 4.24 (2H, s), 4.90 (1H, brs), 6.47 (1H, d, J=16Hz), 7.38 (2H, d, J=8 Hz), 7.43-7.62 (4H, m), 7.73-8.14 (2H, m);

[0509] MASS (ESI): m/z 422 (M+1).

[0510] Preparation 52

[0511] Compound (52) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (384 mg).

[0512]¹H-NMR (300 MHz, DMSO-d, 6): 2.68 (3H, s), 4.55 (2H, s), 6.55 (1H,d, J=16 Hz), 7.50 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.73 (2H, d,J=8 Hz), 7.81 (1H, d, J=8 Hz), 8.04 (1H, dd, J=2, 8 Hz), 8.27 (1H, s);

[0513] MASS (ESI): m/z 321 (M+1).

[0514] Preparation 53

[0515] Compound (53) was obtained from Compound (52) according to amanner similar to Preparation 9 (394 mg). The Compound (53) was used inExample 21.

[0516]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47-1.73 (6H, m), 2.61 (3H, s),3.48-3.57 (1H, m), 3.90-4.01 (1H, m), 4.25 (2H, brs), 4.90 (1H, brs),6.47 (1H, d, J=16 Hz), 7.36-8.23 (8H, m);

[0517] MASS (ESI): m/z 418 (M−1).

[0518] Preparation 54

[0519] Compound (54) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (335 mg).

[0520]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.53 (1H, d, J=16 Hz),7.30-7.36 (1H, m), 7.47 (2H, d, J=8 Hz), 7.54-7.73 (5H, m);

[0521] MASS (ESI): m/z 357 (M+1).

[0522] Preparation 55

[0523] Compound (55) was obtained from Compound (54) according to amanner similar to Preparation 9 (364 mg). The Compound (55) was used inExample 22.

[0524]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48-1.74 (6H, m), 3.48-3.58 (1H,m), 3.89-4.02 (1H, m), 4.24 (2H, s), 4.90 (1H, brs), 6.47 (1H, d, J=16Hz), 7.05-7.12 (1H, m), 7.33-7.58 (7H, m);

[0525] MASS (ESI): m/z 456 (M+1).

[0526] Preparation 56

[0527] Compound (56) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (805 mg).

[0528]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.24 (3H, s), 1.27 (3H, s),3.02-3.15 (1H, m), 4.54 (2H, s), 6.56 (1H, d, J=16 Hz), 7.33-7.75 (8H,m);

[0529] MASS (ESI): m/z 321 (M+1).

[0530] Preparation 57

[0531] Compound (57) was obtained from Compound (56) according to amanner similar to Preparation 9 (70 mg). The Compound (57) was used inExample 23.

[0532]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.22 (3H, s), 1.24 (3H, s),1.48-1.73 (6H, m), 2.89-3.03 (1H, m), 3.48-3.57 (1H, m), 3.89-4.00 (1H,m), 4.17 (2H, s), 4.90 (1H, brs), 6.47 (1H, d, J=16 Hz), 7.01 (1H, d,J=8 Hz), 7.20-7.57 (7H, m);

[0533] MASS (ESI): m/z 420 (M+1).

[0534] Preparation 58

[0535] Compound (58) was obtained from Compound (6) according to mannerssimilar to Preparations 7 and 8 (925 mg).

[0536]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.50 (2H, s), 5.37 (2H, s), 6.54(1H, d, J=16 Hz), 7.13-7.75 (13H, m);

[0537] MASS (ESI): m/z 385 (M+1).

[0538] Preparation 59

[0539] Compound (59) was obtained from Compound (58) according to amanner similar to Preparation 9. The Compound (59) was used in Example24.

[0540] Preparation 60

[0541] Compound (60) was obtained according to a manner similar toPreparation 20 (1.25 g).

[0542]¹H-NMR (300 MHz, CDCl₃, δ): 2.56 (3H, s), 5.27 (2H, s), 6.79(2×1H, d, J=8.4 Hz), 7.15-7.29 (3H, m), 7.63 (2×1H, d, J=8.4 Hz), 7.73(1H, m);

[0543] MASS (ES+): m/e 349.

[0544] Preparation 61

[0545] Compound (61) was obtained from Compound (60) according to amanner similar to Preparation 4 (625 mg).

[0546]¹H-NMR (300 MHz, CDCl₃, δ): 2.57 (3H, s), 5.36 (2H, s), 6.40 (1H,d, J=16.2 Hz), 7.07 (2×1H, d, J=8.5 Hz), 7.20-7.29 (3H, m), 7.48 (2×1H,d, J=8.5 Hz), 7.64 (1H, d, J=16.2 Hz), 7.71 (1H, m);

[0547] MASS (ES+): m/e 293.

[0548] Preparation 62

[0549] Compound (62) was obtained from Compound (61) according to amanner similar to Preparation 9 (556 mg). The Compound (62) was used inExample 25.

[0550]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.75 (6H, m), 2.52 (3H, s),3.52 (1H, m), 3.94 (1H, m), 4.89 (1H, m), 5.50 (2H, s), 6.46 (1H, d,J=16 Hz), 7.11-7.20 (4H, m), 7.38-7.62 (5H, m);

[0551] MASS (ES+): m/e 392.

[0552] Preparation 63

[0553] To a stirred solution of 1-phenylcyclopropanecarboxylic acid(3.25 g) in acetic acid (30 mL) was added periodic acid (959 mg), iodine(2.03 g), concentrated H₂SO₄ (0.6 mL) and water (4 mL), and the mixturewas stirred at 70° C. for 12 hours. Water (100 mL) was added to themixture and the precipitated solid was collected by filtration andwashed with water to give Compound (63) (4.31 g).

[0554]¹H-NMR (300 MHz, CDCl₃, δ): 1.23 (2H, ddd, J=7, 4, 4 Hz), 1.67(2H, ddd, J=7, 4, 4 Hz), 7.09 (2×1H, d, J=8.4 Hz), 7.63 (2×1H, d, J=8.4Hz);

[0555] MASS (ES−): m/e 287.

[0556] Preparation 64

[0557] Compound (64) was obtained from Compound (63) according to amanner similar to Preparation 6 (432 mg).

[0558]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.16 (2H, ddd, J=7, 4, 4 Hz), 1.45(2H, ddd, J=7, 4, 4 Hz), 1.48 (3×3H, s), 6.49 (1H, d, J=15.7 Hz), 7.35(2×1H, d, J=8 Hz), 7.53 (1H, d, J=15.7 Hz), 7.61 (2×1H, d, J=8 Hz);

[0559] MASS (ES−): m/e not determined.

[0560] Preparation 65

[0561] Compound (65) was obtained from Compound (64) according to amanner similar to Preparation 7 (1.67 g).

[0562]¹H-NMR (300 MHz, CDCl₃, δ): 1.20 (2H, m), 1.45 (3×3H, s), 1.51(3×3H, s), 1.74 (2H, m), 6.40 (1H, d, J=15.7 Hz), 6.63 (1H, br-s),6.98-7.62 (10H, m);

[0563] MASS (ES+): m/e 479.

[0564] Preparation 66

[0565] Compound (66) was obtained from Compound (65) according to amanner similar to Preparation 8 (710 mg).

[0566]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.71 (2H, m), 1.95 (2H, m), 6.59(1H, d, J=15.8 Hz), 7.40-7.55 (4H, m), 7.63 (1H, d, J=15.8 Hz),7.64-7.72 (2H, m), 7.76 (2×1H, d, J=8.4 Hz);

[0567] MASS (ES+): m/e 305.

[0568] Preparation 67

[0569] Compound (67) was obtained from Compound (66) according to amanner similar to Preparation 9 (647 mg).

[0570]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.39 (2H, m), 1.48-1.76 (8H, m),3.34 (1H, m), 3.54 (1H, m), 3.96 (1H, m), 4.91 (2H, s), 6.51 (1H, d,J=16 Hz), 7.07-7.15 (2H, m), 7.31-7.43 (3H, m), 7.46-7.63 (4H, m);

[0571] MASS (ES+): m/e 404.

[0572] Preparation 68

[0573] To a stirred solution of 4-bromo-2-nitroaniline (1.37 g) indioxane (20 mL) was added 4-fluorophenylboronic acid (1.06 g),PdCl₂(PPh₃)₂ (133 mg), and 2M sodium carbonate solution (12.7 ml), andthe mixture was stirred at 100° C. for 2 hours. The solvent wasevaporated and the residue was partioned between ethyl acetate andwater. The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The resulting solid was recrystalized fromtoluene to give Compound (68) (1.13 g) as a white solid.

[0574]¹H-NMR (300 MHz, CDCl₃, δ): 6.18 (2H, br-s), 6.89 (1H, d, J=8.7Hz), 7.12 (2×1H, dd, J=8-0.7, 8.7 Hz), 7.51 (2×1H, dd, J=8.7, 5 Hz),7.59 (1H, dd, J=8.7, 2.2 Hz), 8.31 (1H, d, J=2.2 Hz);

[0575] MASS (ES−) m/e 231.

[0576] Preparation 69

[0577] To a stirred solution of Compound (68) (1.08 g) in EtOH (15 mL)was added tin (II) chloride (1.32 g) The mixture was stirred at 100° C.for 6 hours. The solvent was evaporated to the half volume and theresidue was basified with 1N-NaOH to pH 9 and extracted with ethylacetate. The organic phase was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was triturated with ethyl acetate togive Compound (69) (800 mg) as an orange powder.

[0578]¹H-NMR (300 MHz, CDCl₃, δ): 3.45 (2×2H, br-s), 6.76 (2×1H, d,J=8.3 Hz), 6.89 (1H, d, J=2.1 Hz), 6.91 (1H, dd, J=8.3, 2.1 Hz), 7.06(2×1H, dd, J=8.8, 8.8 Hz), 7.46 (2×1H, dd, J=8.8, 5.4 Hz);

[0579] MASS (ES+): m/e 203.

[0580] Preparation 70

[0581] Compound (70) was obtained from Compound (69) according to amanner similar to Preparation 7 (552 mg).

[0582]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (3×3H, s), 3.81 (2H, s), 6.39(1H, sd, J=16 Hz), 6.80-7.62 (15H, m);

[0583] MASS (ES+): m/e 446.

[0584] Preparation 71

[0585] Compound (71) was obtained from Compound (70) according to amanner similar to Preparation 8 (375 mg).

[0586]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.56 (1H, d, J=16 Hz),7.23-7.86 (11H, m), 7.94 (1H, s);

[0587] MASS (ES+): m/e 373.

[0588] Preparation 72

[0589] Compound (72) was obtained from Compound (71) according to amanner similar to Preparation 9 (321 mg). The Compound (71) was used inExample 26.

[0590]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.75 (6H, m), 3.52 (1H, m),3.95 (1H, m), 4.22 (2H, s), 4.90 (1H, m), 6.48 (1H, d, J=15.8 Hz),7.22-7.80 (12H, m), 11.23 (1H, br-s), 12.40 (H, br-s);

[0591] MASS (ES+): m/e 472.

[0592] Preparation 73

[0593] Compound (73) was obtained from Compound (6) according to amanner similar to Preparation 7 (228 mg).

[0594]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3×3H, s), 3.75-3.87 (4H, br),6.41 (1H, d, J=15.7 Hz), 6.81-7.54 (13H, m), 7.58 (1H, d, J=15.7 Hz);

[0595] MASS (ES+): m/e 429.

[0596] Preparation 74

[0597] Compound (74) was obtained from Compound (73) according to amanner similar to Preparation 8 (165 mg).

[0598]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.59 (2H, s), 6.59 (1H, d, J=16 Hz),7.38-7.55 (5H, m), 7.59 (1H, d, J=16 Hz), 7.67 (1H, m), 7.73 (2×1H, d,J=7.5 Hz), 7.78-7.85 (2H, m), 7.87 (1H, br), 7.96 (1H, br-s);

[0599] MASS (ES+): m/e 355.

[0600] Preparation 75

[0601] Compound (75) was obtained from Compound (74) according to amanner similar to Preparation 9 (185 mg). The Compound (75) was used inExample 27.

[0602]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.76 (6H, m), 3.53 (1H, m),3.94 (1H, m), 4.23 (2H, s), 4.90 (1H, m), 6.50 (1H, d, J=16 Hz),7.28-7.52 (10H, m), 7.57 (1H, m), 7.66 (2×1H, d, J=7.5 Hz), 11.25 (1H,br), 12.38 (1H, br);

[0603] MASS (ES+): m/e 454.

[0604] Preparation 76

[0605] Compound (76) was obtained according to a manner similar toPreparation 35 (320 mg).

[0606]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.24 (3H, s), 7.16 (1H, d, J=8.8Hz), 7.68 (2H, s), 7.85-8.07 (5H, m), 8.34 (1H, d, J=2.5 Hz);

[0607] MASS (ES−): m/e 291.

[0608] Preparation 77

[0609] To a stirred solution of4′-(methylsulfonyl)-3-nitro-1,1′-biphenyl-4-ylamine (305 g) in EtOH (15mL) was added iron powder (583 mg), NH₄Cl (56 mg) and water (1 mL). Themixture was refluxed for 5 hours. The iron powder was filtered off andthe filtrate was evaporated in vacuo. The residue was partioned betweenCHCl₃ and saturated NaHCO₃ solution. The organic phase was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give Compound(77) (150 mg) as an orange powder.

[0610]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.44 (3H, s), 4.45-5.20 (4H, m),6.65 (1H, br), 6.82-7.22 (2H, m), 7.62-8.22 (4H, m);

[0611] MASS (ES+): m/e 263.

[0612] Preparation 78

[0613] Compound (78) was obtained from Compound (77) according to amanner similar to Preparation 7 (200 mg).

[0614]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (3×3H, s), 3.07 (3×½H, s), 3.08(3×½H, s), 3.83 (2H, br-s), 6.39 (1H, d, J=16 Hz), 6.84-7.10 (2H, m),7.29 (1H, m), 7.42 (2H, m), 7.53-7.73 (5H, m), 7.95 (2H, m);

[0615] MASS (ES+): m/e 507.

[0616] Preparation 79

[0617] Compound (79) was obtained from Compound (78) according to amanner similar to Preparation 8 (162 mg).

[0618]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.28 (3H, s), 4.59 (2H, s), 6.57(1H, d, J=15.8 Hz), 7.52 (2×1H, d, J=8.2 Hz), 7.59 (1H, d, J=15.8 Hz),7.74 (2×1H, d, J=8.2 Hz), 7.86-7.90 (2H, m), 7.95-8.10 (5H, m);

[0619] MASS (ES+): m/e 432.

[0620] Preparation 80

[0621] Compound (80) was obtained from Compound (79) according to amanner similar to Preparation 9 (190 mg). The Compound (80) was used forExample 28.

[0622]¹H-NMR (300 MHz, DMSO-d, 6): 1.46-1.76 (6H, m), 3.25 (3H, s), 3.53(1H, m), 3.94 (1H, m), 4.24 (2H, m), 4.90 (1H, m), 6.48 (1H, d, J=16Hz), 7.39 (2×1H, d, J=8 Hz), 7.42-8.02 (10H, m), 11.23 (0.5H, br), 12.50(0.5H, br);

[0623] MASS (ES+): m/e 532.

[0624] Preparation 81

[0625] Compound (81) was obtained from Compound (6) according to amanner similar to Preparation 7 (137 mg).

[0626]¹H-NMR (300 MHz, CDCl₃, δ): 1.33 (3H, t, J=7.5 Hz), 4.26 (2H, q,J=7.5 Hz), 4.38 (2H, s), 6.41 (1H, d, J=16 Hz), 7.18 (1H, dd, J=8, 4.5Hz), 7.38 (2×1H, d, J=8 Hz), 7.51 (2×1H, d, J=8 Hz), 7.65 (1H, d, J=16Hz), 7.99-8.10 (2H, m);

[0627] MASS (ES+): m/e 308.

[0628] Preparation 82

[0629] Compound (82) was obtained from Compound (81) according to amanner similar to Preparation 12 (362 mg).

[0630]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.23 (2H, s), 6.50 (1H, d, J=16 Hz)7.17 (1H, dd, J=8, 5 Hz), 7.38 (2×1H, d, J=8 Hz), 7.56 (1H, d, J=16 Hz),7.65 (2×1H, d, J=8 Hz), 7.91 (1H, br), 8.25 (1H, br);

[0631] MASS (ES+): m/e 280.

[0632] Preparation 83

[0633] Compound (83) was obtained from Compound (82) according to amanner similar to Preparation 9 (312 mg). The Compound (83) was used inExample 29.

[0634]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.76 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.21 (2H, br-s), 4.90 (1H, m), 6.48 (1H, d, J=15.5 Hz),7.17 (1H, dd, J=8, 4.5 Hz), 7.39 (2×1H, d, J=8 Hz), 7.46 (1H, d, J=15.5Hz), 7.54 (2×1H, br-d, J=8 Hz), 7.88 (1H, m), 8.27 (1H, m), 11.24 (1H,br-s), 12.58 (0.5H, br), 13.00 (0.5H, br);

[0635] MASS (ES+): m/e 379.

[0636] Preparation 84

[0637] Compound (84) was obtained from Compound (6) according to amanner similar to Preparation 7 (9.77 g).

[0638]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.26 (3H, t, J=7 Hz), 3.74 (2H, s),4.19 (2H, q, J=7 Hz), 6.54 (2H, s), 6.62 (1H, d, J=16 Hz), 6.77 (1H, d,J=8.8 Hz), 7.41 (2×1H, d, J=8 Hz), 7.65 (1H, d, J=16 Hz), 7.70 (2×1H, d,J=8 Hz), 7.85 (1H, dd, J=8.8, 2.5 Hz), 8.20 (1H, d, J=2.5 Hz), 9.46 (1H,s);

[0639] MASS (ES+):: m/e 370.

[0640] Preparation 85

[0641] Compound (85) was obtained from Compound (84) according to amanner similar to Preparation 8 (6.83 g).

[0642]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.25 (3H, t, J=7 Hz), 4.18 (2H, q,J=7 Hz), 4.44 (2H, s), 6.64 (1H, d, J=16 Hz), 7.46 (2×1H, d, J=8 Hz),7.64 (1H, d, J=16 Hz), 7.73 (2×1H, d, J=8 Hz), 7.80 (1H, d, J=9 Hz),8.20 (1H, dd, J=9, 2.2 Hz), 8.50 (1H, d, J=2.2 Hz);

[0643] MASS (ES+): m/e 352.

[0644] Preparation 86

[0645] Compound (86) was obtained from Compound (85) according to amanner similar to Preparation 77 (872 mg).

[0646]¹H-NMR (300 MHz, CDCl₃, δ): 1.31 (3H, br-t, J=7 Hz), 4.15-4.36(4H, m), 6.26 (1H, br-d, J=16 Hz), 6.64 (1H, m), 6.78 (1H, m), 7.20-7.40(5H, m), 7.49 (1H, br-d, J=16 Hz);

[0647] MASS (ES+): m/e 322.

[0648] Preparation 87

[0649] To a stirred suspension of Compound (86) (303 mg) in dioxane (10mL) was added di-tert-butyldicarbonate (618 mg) in dioxane (3 mL) andthen 1N-NaOH (2.8 mL), and the mixture was stirred at ambienttemperature for 12 hours. The solvent was evaporated in vacuo and theresidue was partioned between ethyl acetate and water. The organic phasewas washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography(hexane:ethyl acetate=1:1) to give Compound (87) (379 mg) as a palebrown amorphous (379 mg).

[0650]¹H-NMR (300 MHz, CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 1.52 (4.5H, s),1.53 (4.5H, s), 1.58 (4.5H, s), 1.60 (4.5H, s), 4.25 (2H, q, J=7 Hz),4.61 (2H, s), 6.39 (1H, d, J=16 Hz), 6.58 (1H, br-d, J=6 Hz), 7.09(0.5H, dd, J=8.8, 2.2 Hz), 7.23-7.30 (2H, m), 7.42-7.48 (2.5H, m),7.567.68 (2H, m), 7.77 (0.5H, d, J=8.8 Hz), 8.24 (0.5H, br);

[0651] MASS (ES+): m/e 522.

[0652] Preparation 88

[0653] To a stirred solution of Compound (87) (360 mg) in methanol (5m]L) was added 1N-NaOH solution (1.4 mL). The mixture was stirred atambient temperature for 2.5 hours. The reaction mixture was neutralizedby 1N—HCl solution, and the solvent was evaporated in vacuo. The residuewas partioned between ethyl acetate and water. The oraganic phase waswashed with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (88) (57 mg) as an orangepowder and a methyl ester of Compound (88) as a by-product.

[0654]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (3×3H, s), 4.16 (2H, s), 6.49(1H, d, J=16 Hz), 7.12 (1H, br), 7.31-7.42 (3H, m), 7.55 (1H, d, J=16Hz), 7.60-7.72 (3H, m), 9.25 (1H, br), 12.12 (1H, br);

[0655] MASS (ES+): m/e 394.

[0656] Preparation 89

[0657] Compound (89) was obtained from the metyl ester of Compound (88)according to a manner similar to Preparation 12 (245 mg). [The Compound(89) is similar to Compound (88).]

[0658]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (3×3H, s), 4.22 (2H, s), 6.50(1H, d, J=16 Hz), 7.19 (1H, br-d, J=8.5 Hz), 7.34-7.42 (3H, m), 7.56(1H, d, J=16 Hz), 7.65 (2×1H, d, J=8.5 Hz), 7.72 (1H, br-s), 9.30 (1H,br-s), 12.38 (1H, br);

[0659] MASS (ES+): m/e 394.

[0660] Preparation 90

[0661] Compound (90) was obtained from Compound (88) according to amanner similar to Preparation 9 (230 mg). The Compound (90) was used forExample 30.

[0662]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (3×3H, s), 1.48-1.75 (6H, m),3.53 (1H, m), 3.94 (1H, m), 4.15 (2H, s), 4.90 (1H, m), 6.47 (1H, br-d,J=16 Hz), 7.06-7.414 (4H, m), 7.46 (1H, d, J=16 Hz), 7.53 (2×1H, br-d,J=8.5 Hz), 7.67 (1H, m), 9.15 (1/3H, br-s), 9.26 (2/3H, br-s), 11.22(1H, br-s), 12.10 (2/3H, br-s), 12.13 (1/3H, br-s);

[0663] MASS (ES+): m/e 493.

[0664] Preparation 91

[0665] To a stirred solution of Compound (86) (150 mg) in DMF (2 mL) wasadded butyric acid (49 mg), HOBT (76 mg), and EDCI hydrochloride (107mg), and the resulting mixture was stirred at ambient temperature for 12hours. The reaction mixture was diluted with ethyl acetate and washedsuccessively with water, saturated NaHCO₃ solution and brine. Theorganic phase was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (91) (30 mg) as a paleyellow amorphous.

[0666]¹H-NMR (300 MHz, CDCl₃, δ): 0.98 (3H, t, J=7.3 Hz), 1.33 (3H, t,J=7 Hz), 1.73 (2H, tq, J=7.3, 7.3 Hz), 2.33 (2H, t, J=7.3 Hz), 4.09 (2H,s), 4.24 (2H, q, J=7 Hz), 6.31 (1H, d, J=16 Hz), 7.05 (1H, br-d, J=8Hz), 7.15 (2×1H, d, J=8 Hz), 7.32 (2×1H, d, J=8 Hz), 7.36 (1H, d, J=8Hz), 7.53 (1H, s), 7.58 (1H, s);

[0667] MASS (ES+): m/e 392.

[0668] Preparation 92

[0669] Compound (92) was obtained from Compound (91) according to amanner similar to Preparation 11 (28 mg).

[0670]¹H-NMR (300 MHz, CD₃OD, δ): 1.00 (3H, t, J=7.3 Hz), 1.73 (2H, tq,J=7.3, 7.3 Hz), 2.42 (2H, t, J=7.3 Hz), 4.58 (2H, s), 6.52 (1H, d, J=16Hz), 7.47-7.58 (3H, m), 7.64-7.74 (4H, m), 8.29 (1H, s);

[0671] MASS (ES+): m/e 364.

[0672] Preparation 93

[0673] Compound (93) was obtained from Compound (92) according to amanner similar to Preparation 9 (19 mg). The Compound (93) was used inExample 31.

[0674]¹H-NMR (300 MHz, CD₃OD-CDCl₃, δ): 1.00 (3H, t, J=7.4 Hz),1.52-1.96 (8H, m), 2.35 (2H, t, J=7.5 Hz), 3.65 (1H, m), 4.03 (1H, m),4.11 (2H, s), 5.03 (1H, m), 6.24 (1H, m), 7.06-7.29 (4H, m), 7.38 (2×1H,d, J=8.5 Hz), 7.48 (1H, m), 7.82 (1H, s);

[0675] MASS (ES+): m/e 463.

[0676] Preparation 94

[0677] Compound (94) was obtained from Compound (6) according to amanner similar to Preparation 7 (641 mg).

[0678]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.26 (3H, t, J=7 Hz), 3.76 (2H, s),4.19 (2H, q, J=7 Hz), 6.62 (1H, d, J=16 Hz), 6.64 (1H, dd, J=8.5, 8.5Hz), 7.12 (2H, s), 7.40 (2×1H, d, J=8.5 Hz), 7.45 (1H, dd, J=8.5, 1 Hz),7.65 (1H, d, J=16 Hz), 7.69 (2×1H, d, J=8.5 Hz), 7.91 (1H, dd, J=8.5, 1Hz), 9.57 (1H, s);

[0679] MASS (ES+): m/e 370.

[0680] Preparation 95

[0681] Compound (95) was obtained from Compound (94) according to amanner similar to Preparation 8 (512 mg).

[0682]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.25 (3H, t, J=7 Hz), 4.18 (2H, q,J=7 Hz), 4.45 (2H, s), 6.62 (1H, d, J=16 Hz), 7.46 (2×1H, d, J=8.3 Hz),7.49 (1H, dd, J=8, 8 Hz), 7.63 (1H, d, J=16 Hz), 7.71 (2×1H, d, J=8.3Hz), 8.11 (1H, d, J=8 Hz), 8.20 (1H, d, J=8 Hz);

[0683] MASS (ES+): m/e 352.

[0684] Preparation 96

[0685] Compound (96) was obtained from Compound (95) according to amanner similar to Preparation 12 (119 mg).

[0686]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.34 (2H, s), 6.49 (1H, d, J=16 Hz),7.36 (1H, dd, J=8, 8 Hz), 7.41 (2×1H, d, J=8 Hz), 7.55 (1H, d, J=16 Hz),7.64 (2×1H, d, J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.09 (1H, d, J=8 Hz).,13.26 (1H, br-s);

[0687] MASS (ES+): m/e 324.

[0688] Preparation 97

[0689] Compound (97) was obtained from Compound (96) according to amanner similar to Preparation 9 (70 mg). The Compound (97) was used inExample 32.

[0690]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.77 (6H, m), 3.53 (1H, m) 3.95(1H, m), 4.34 (2H, s), 4.90 (1H, m), 6.47 (1H, d, J=16 Hz), 7.37 (1H,dd, J=8, 8 Hz), 7.42 (2×1H, d, J=8 Hz), 7.46 (1H, d, J=16 Hz), 7.53(2×1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.10 (1H, d, J=8 Hz);

[0691] MASS (ES+): m/e 423.

[0692] Preparation 98

[0693] Compound (98) was obtained from Compound (6) according to amanner similar to Preparation 7 (160 mg).

[0694]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.26 (3H, t, J=7 Hz), 3.75 (2H, s),4.19 (2H, q, J=7 Hz), 6.47 (2H, br-s), 6.62 (1H, d, J=16 Hz), 6.70 (1H,d, J=6 Hz), 7.40 (2×1H, d, J=8 Hz), 7.65 (1H, d, J=16 Hz), 7.69 (2×1H,d, J=8 Hz), 7.91 (1H, d, J=6 Hz), 8.18 (1H, s), 9.61 (1H, s);

[0695] MASS (ES+): m/e 326.

[0696] Preparation 99

[0697] Compound (99) was obtained from Compound (6) according to amanner similar to Preparation 8 (91 mg).

[0698]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.26 (2H, s), 6.50 (1H, d, J=16 Hz),7.38 (2×1H, d, J=8 Hz), 7.48 (1H, m), 7.56 (1H, d, J=16 Hz), 7.65 (2×1H,d, J=8 Hz), 8.25 (1H, d, J=3 Hz), 8.81 (1H, s), 12.75 (1H, br);

[0699] MASS (ES+): m/e 280.

[0700] Preparation 100

[0701] Compound (100) was obtained from Compound (99) according to amanner similar to Preparation 9 (33 mg). The Compound (100) was used forExample 33.

[0702]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.40-1.80 (6H, m), 3.52 (1H, m),3.96 (1H, m), 4.26 (2H, s), 4.91 (1H, m), 6.50 (1H, br-d, J=15.5 Hz),7.35-7.60 (6H, m), 8.22 (1H, d, J=5.5 Hz), 8.81 (1H, s);

[0703] MASS (ES+) m/e 379.

[0704] Preparation 101

[0705] Compound (101) was obtained from Compound (6) according to amanner similar to Preparation 7 (520 mg).

[0706]¹H-NMR (300 MHz, DMSO-d, 6): 1.26 (3H, t, J=7 Hz), 3.11 (3H, s),3.31 (3H, s), 3.62 (2H, s), 4.19 (2H, q, J=7 Hz), 6.54-6.68 (3H, m),7.41 (2×1H, d, J=8 Hz), 7.58-7.70 (3H, m), 8.66 (1H, s);

[0707] MASS (ES+): m/e 387.

[0708] Preparation 102

[0709] Compound (102) was obtained from Compound (101) according to amanner similar to Preparation 8 (416 mg).

[0710]¹H-NMR (300 MHz, DMSO-d, 6): 3.22 (3H, s), 3.40 (3H, s), 4.08 (2H,s), 6.49 (1H, d, J=16 Hz), 7.33 (2×1H, d, J=8.3 Hz), 7.55 (1H, d, J=16Hz), 7.64 (2×1H, d, J=8.3 Hz), 12.39 (1H, s), 13.48 (1H, s);

[0711] MASS (ES+): m/e 341.

[0712] Preparation 103

[0713] Compound (103) was obtained from Compound (102) according to amanner similar to Preparation 9 (254 mg). The Compound (103) was used inExample 34.

[0714]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.76 (6H, m), 3.22 (3H, s),3.40 (3H, s), 3.53 (1H, m), 3.95 (1H, m), 4.07 (2H, s), 4.90 (1H, m),6.47 (1H, d, J=16 Hz), 7.33 (2×1H, d, J=7.5 Hz), 7.46 (1H, d, J=16 Hz),7.53 (2×1H, d, J=7.5 Hz), 11.23 (1H, br-s), 13.47 (1H, br-s);

[0715] MASS (ES−): m/e 438.

[0716] Preparation 104

[0717] Compound (104) was obtained from Compound (85) according to amanner similar to Preparation 12 (1.54 g).

[0718]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.38 (2H, s), 6.52 (1H, d, J=16.2Hz), 7.42 (2×1H, d, J=8 Hz), 7.57 (1H, d, J=16.2 Hz), 7.68 (2×1H, d, J=8Hz), 7.74 (1H, d, J=8.8 Hz), 8.14 (1H, dd, J=8.8, 2.2 Hz), 8.46 (1H, d,J=2.2 Hz);

[0719] MASS (ES+): m/e 324.

[0720] Preparation 105

[0721] Compound (105) was obtained from Compound (104) according to amanner similar to Preparation 9 (1.42 g). The Compound (105) was used inExample 35.

[0722]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.76 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.30 (2H, s), 4.90 (1H, m), 6.48 (1H, d, J=15.8 Hz), 7.39(2×1H, d, J=8.5 Hz), 7.47. (1H, d, J=15.8 Hz), 7.55 (2×1H, d, J=8.5 Hz),7.67 (1H, d, J=8.8 Hz), 8.08 (2×1H, d, J=8.8 Hz), 8.41 (1H, d, J=2.2Hz), 11.25 (1H, br), 13.02 (1H, br);

[0723] MASS (ES+): m/e 423.

[0724] Preparation 106

[0725] Thionyl chloride (1.75 mL) was dropwise added under stirring tomethanol at 0° C. After 30 minutes 4-hydroxycinnamic acid (3.29 g) wasadded and the mixture was refluxed for 1.5 h. The solvent was evaporatedin vacuo and the residue was crystalized from diisopropyl ether andhexane to give Compound (106) (2.41 g) as a white crystal.

[0726]¹H-NMR (300 MHz, CDCl₃, δ): 3.80 (3H, s), 5.44 (1H, s), 6.31 (1H,d, J=16 Hz), 6.85 (2×1H, d, J=8.5 Hz), 7.43 (2×1H, d, J=8.5 Hz), 7.64(1H, d, J=16 Hz);

[0727] MASS (ES−): m/e 177.

[0728] Preparation 107

[0729] To a stirred solution of Compound (106) (609 mg) indimethylformamide (15 mL) was added sodium hydride (164 mg, 60% oildispersion) at 0° C. After 30 minutes, tert-butyl bromoacetate (733 mg)was added dropwise, and the mixture was stirred at ambient temperaturefor 2 hours. The resulting mixture was poured into 10% citric acidsolution and extracted with ethyl acetate. The organic phase was washedwith saturated NaHCO₃ solution and brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by chromatography(hexane:ethyl acetate=4:1) to give Compound (107) (962 mg) as a solid.

[0730]¹H-NMR (300 MHz, CDCl₃, δ): 1.49 (3×3H, s), 3.80 (3H, s), 4.55(2H, s), 6.32 (1H, d, J=15.8 Hz), 6.90 (2×1H, d, J=8.8 Hz), 7.47 (2×1H,d, J=8.8 Hz), 7.65 (1H, d, J=15.8 Hz);

[0731] MASS (ES+): m/e not detected.

[0732] Preparation 108

[0733] A solution of Compound (107) (906 mg) in 0.5 N-hydrogen chloridein acetic acid (10 mL) was heated at 60° C. for 2 hours. The solvent wasevaporated in vacuo and the residue was triturated with diisopropylether to give Compound (108) (645 mg) as a white solid.

[0734]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.71 (3H, s), 4.74 (2H, s), 6.51(1H, d, J=16 Hz), 6.96 (2×1H, d, J=8.5 Hz), 7.62 (1H, d, J=16 Hz), 7.67(2×1H, d, J=8.5 Hz), 13.07 (1H, br-s);

[0735] MASS (ES−): m/e 235.

[0736] Preparation 109

[0737] Compound (109) was obtained from Compound (108) according to amanner similar to Preparation 7 (950 mg).

[0738]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45 (3×3H, s), 3.71 (3H, s), 4.79(2H, s), 6.53 (1H, d, J=16 Hz), 7.07 (2×1H, d, J=8.8 Hz), 7.08-7.20 (2H,m), 7.46 (1H, m), 7.56 (1H, m), 7.63 (1H, d, J=16 Hz), 7.72 (2×1H, d,J=8.8 Hz), 8.73 (1H, br-s), 9.55 (1H, br-s);

[0739] MASS (ES+): m/e 427.

[0740] Preparation 110

[0741] Compound (110) was obtained from Compound (109) according to amanner similar to Preparation 8 (800 mg).

[0742]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.71 (3H, s), 5.69 (2H, s), 6.56(1H, d, J=16 Hz), 7.20 (2×1H, d, J=8.8 Hz), 7.49-7.57 (2H, m), 7.65 (1H,d, J=16 Hz), 7.73-7.85 (4H, m);

[0743] MASS (ES+): m/e 309.

[0744] Preparation 111

[0745] Compound (111) was obtained from Compound (110) according to amanner similar to Preparation 12 (580 mg).

[0746]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.45 (2H, s), 6.41 (1H, d, J=16 Hz),7.14 (2×1H, d, J=8.8 Hz), 7.23-7.32 (2H, m), 7.55 (1H, d, J=16 Hz),7.56-7.66 (2H, m), 7.68 (2×1H, d, J=8.8 Hz), 12.28 (1H, br);

[0747] MASS (ES+): m/e 295.

[0748] Preparation 112

[0749] Compound (112) was obtained from Compound (111) according to amanner similar to Preparation 9 (503 mg). The Compound (112) was used inExample 36.

[0750]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47-1.76 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.89 (1H, m), 5.37 (2H, s), 6.37 (1H, d, J=16 Hz),7.10-7.25 (4H, m), 7.39-7.67 (5H, m), 11.16 (1H, s), 12.68 (1H, s);

[0751] MASS (ES+): m/e 394.

[0752] Preparation 113

[0753] To a stirred solution of Compound (86) (165 mg) in methanol (3mL) were added cyclopentanone (52 mg) and sodium cyanoborohydride (39mg). To the mixture was added acetic acid so that final pH was set to 5.The mixture was stirred at ambient temperature for 2 hours. Theresulting mixture was poured into water and extracted with ethylacetate. The organic phase was washed with brine, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer chromatography (chloroform:methanol=10:1) to giveCompound (113) (140 mg) as a brown oil.

[0754]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7.3 Hz), 1.40-1.77 (6H,m), 1.95-2.08 (2H, m), 3.76 (1H, m), 4.24 (2H, s), 4.26 (2H, q, J=7.3Hz), 6.41 (1H, d, J=16 Hz), 6.56 (1H, dd, J=7, 2.2 Hz), 6.64 (1H, s),7.31 (2×1H, d, J=8 Hz), 7.36 (1H, d, J=8.8 Hz), 7.48 (2×1H, d, J=8 Hz),7.65 (1H, d, J=16 Hz);

[0755] MASS (ES+): m/e 390.

[0756] Preparation 114

[0757] Compound (114) was obtained from Compound (113) according to amanner similar to Preparation 12 (91 mg).

[0758]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.36-1.76 (6H, m), 1.89 (2H, m),4.08 (2H, s), 6.44-6.56 (3H, m), 7.17 (1H, m), 7.34 (2×1H, d, J=8 Hz),7.55 (1H, d, J=16 Hz), 7.62 (2×1H, d, J=8 Hz), 11.72 (1H, br);

[0759] MASS (ES+): m/e 362.

[0760] Preparation 115

[0761] Compound (115) was obtained from Compound (114) according to amanner similar to Preparation 9 (40 mg). The Compound (115) was used inExample 37.

[0762]¹H-NMR (300 MHz, CDCl₃, δ): 1.38-2.08 (14H, m), 3.62 (1H, m), 3.75(1H, m), 4.00 (1H, m), 4.11 (2H, s), 5.08 (1H, m), 6.20 (1H, br), 6.56(1H, d, J=8 Hz), 6.68 (1H, s), 6.94-7.55 (6H, m);

[0763] MASS (ES+): m/e 461.

[0764] Preparation 116

[0765] Compound (116) was obtained according to a manner similar toPreparation 106 (1.77 g).

[0766]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.72 (3H, s), 6.53 (1H, d, J=16 Hz),6.84 (1H, br-dd, J=8, 2 Hz), 7.04 (1H, br-d, J=2 Hz), 7.14 (1H, br-d,J=8 Hz), 7.22 (1H, dd, J=8, 8 Hz), 7.57 (1H, d, J=16 Hz), 9.63 (1H, s);

[0767] MASS (ES−): m/e 177.

[0768] Preparation 117

[0769] Compound (117) was obtained from Compound (116) according to amanner similar to Preparation 107 (1.61 g).

[0770]¹H-NMR (300 MHz, CDCl₃, δ): 1.49 (3×3H, s), 3.81 (3H, s), 4.54(2H, s), 6.41 (1H, d, J=16 Hz), 6.92 (1H, dd, J=8, 2.5 Hz), 7.04 (1H,dd, J=2.5, 2.5 Hz), 7.15 (1H, br-d, J=8 Hz), 7.31 (1H, dd, J=8, 8. Hz),7.64 (1H, d, J=16 Hz);

[0771] MASS (ES+): m/e not detected.

[0772] Preparation 118

[0773] Compound (118) was obtained from Compound (117) according to amanner similar to Preparation 8 (1.25 g).

[0774]¹H-NMR (300 MHz, CDCl₃, δ): 3.82 (3H, s), 4.72 (2H, s), 6.43 (1H,d, J=16 Hz), 6.96 (1H, dd, J=8, 2.5 Hz), 7.07 (1H, br-s), 7.20 (1H,br-d, J=8 Hz), 7.34 (1H, dd, J=8, 8 Hz), 7.65 (1H, d, J=16 Hz);

[0775] MASS (ES−): m/e 235.

[0776] Preparation 119

[0777] Compound (119) was obtained from Compound (118) according to amanner similar to Preparation 7 (1.92 g).

[0778]¹H-NMR (300 MHz, CDCl₃, δ): 1.49 (3×3H, s), 3.82 (3H, s), 4.69(2H, s), 6.45 (1H, d, J=16 Hz), 6.69 (1H, br-s), 7.03 (1H, dd, J=8, 2.5Hz), 7.15-7.26 (4H, m), 7.37 (1H, dd, J=8, 8 Hz), 7.41 (1H, m), 7.63(1H, m), 7.66 (1H, d, J=16 Hz), 9.00 (1H, br-s);

[0779] MASS (ES+): m/e 427.

[0780] Preparation 120

[0781] Compound (120) was obtained from Compound (119) according to amanner similar to Preparation 8 (1.67 g).

[0782]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.74 (3H, s), 5.68 (2H, s), 6.74(1H, d, J=16 Hz), 7.21 (1H, m), 7.40-7.46 (2H, m), 7.49-7.59 (3H, m),7.68 (1H, d, J=16 Hz), 7.77-7.85 (2H, m);

[0783] MASS (ES+): m/e 309.

[0784] Preparation 121

[0785] Compound (121) was obtained from Compound (120) according to amanner similar to Preparation 12 (1.24 g).

[0786]¹H-NMR (300 MHz, DMSO-d, 6): 5.37 (2H, s), 6.58 (1H, d, J=16 Hz),7.11-7.26 (3H, m), 7.27-7.40 (2H, m), 7.45 (1H, br-s), 7.50 (1H, m),7.57 (1H, d, J=16 Hz), 7.63 (1H, m), 12.69 (1H, s);

[0787] MASS (ES+): m/e 295.

[0788] Preparation 122

[0789] Compound (122) was obtained from Compound (120) according to amanner similar to Preparation 9 (1662 mg). The Compound (122) was usedin Example 38.

[0790]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.78 (6H, m), 3.54 (1H, m),3.96 (1H, m), 4.91 (1H, m), 5.36 (2H, s), 6.53 (1H, d, J=16 Hz), 7.12(1H, dd, J=8, 2.5 Hz), 7.15-7.26 (3H, m), 7.32 (1H, br-s), 7.36 (1H, dd,J=8, 8 Hz), 7.46-7.68 (2H, m), 7.47 (1H, d, J=16 Hz), 11.27 (1H, br-s),12.69 (1H, br-s);

[0791] MASS (ES+): m/e 394.

[0792] Preparation 123

[0793] Compound (123) was obtained from Compound (86) according to amanner similar to Preparation 113 (415 mg).

[0794]¹H-NMR (300 MHz, CDCl₃, δ): 1.12 (2×3H, t, J=7 Hz), 1.34 (3H, t,J=7 Hz), 3.34 (2×2H, q, J=7 Hz), 4.23 (2H, s), 4.26 (2H, q, J=7 Hz),6.39 (1H, d, J=16 Hz), 6.79 (1H, dd, J=9, 2 Hz), 6.91 (1H, d, J=2 Hz),7.30 (2×1H, d, J=8 Hz), 7.44 (1H, d, J=9 Hz), 7.45 (2×1H, d, J=8 Hz),7.63 (1H, d, J=16 Hz);

[0795] MASS (ES+): m/e 378.

[0796] Preparation 124

[0797] Compound (124) was obtained from Compound (123) according to amanner similar to Preparation 12 (227 mg).

[0798]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.05 (2×3H, t, J=7 Hz), 3.28 (2×2H,q, J=7 Hz), 4.12 (2H, s), 6.49 (1H, d, J=16 Hz), 6.61-6.72 (2H, m), 7.28(1H, br-d, J=8 Hz), 7.35 (2×1H, d, J=8 Hz), 7.56 (1H, d, J=16 Hz), 7.63(2×1H, d, J=8 Hz), 11.82 (1H, br-s);

[0799] MASS (ES+): m/e 350.

[0800] Preparation 125

[0801] Compound (125) was obtained from Compound (124) according to amanner similar to Preparation 9 (132 mg). The Compound (125) was used inExample 39.

[0802]¹H-NMR (300 MHz, CDCl₃, δ): 1.12 (2×3H, t, J=7 Hz), 1.50-1.92 (6H,m), 3.32 (2×3H, q, J=7 Hz), 3.62 (1H, m), 4.00 (1H, m), 4.15 (2H, br-s),5.07 (1H, m), 6.22 (1H, br), 6.71-6.83 (2H, m), 6.96-7.28 (3H, m),7.38-7.54 (3H, m);

[0803] MASS (ES+): m/e 449.

[0804] Preparation 126

[0805] Compound (126) was obtained according to a manner similar toPreparation 106 (4.19 g).

[0806]¹H-NMR (300 MHz, CDCl₃, δ): 3.80 (3H, s), 3.93 (3H, s), 5.85 (1H,br-s), 6.30 (1H, d, J=16 Hz), 6.92 (1H, d, J=8 Hz), 7.03 (1H, d, J=2Hz), 7.08 (1H, dd, J=8, 2 Hz), 7.63 (1H, d, J=16 Hz);

[0807] MASS (ES+): m/e not detected.

[0808] Preparation 127

[0809] Compound (127) was obtained from Compound (126) according to amanner similar to Preparation 107 (5.16 g).

[0810]¹H-NMR (300 MHz, CDCl₃, δ): 1.47 (3×3H, s), 3.80 (3H, s), 3.92(3H, s), 4.62 (2H, s), 6.32 (1H, d, J=16 Hz), 6.76 (1H, d, J=8.7 Hz),7.04-7.09 (2H, m), 7.63 (1H, d, J=16 Hz);

[0811] MASS (ES+): m/e not detected.

[0812] Preparation 128

[0813] Compound (128) was obtained from Compound (127) according to amanner similar to Preparation 8 (4.28 g).

[0814]¹H-NMR (300 MHz, CDCl₃, δ): 3.81 (3H, s), 3.93 (3H, s), 4.74 (2H,s), 6.35 (1H, d, J=16 Hz), 6.89 (1H, d, J=9 Hz), 7.07-7.12 (2H, m), 7.63(1H, d, J=16 Hz);

[0815] MASS (ES−): m/e 265.

[0816] Preparation 129

[0817] Compound (129) was obtained from Compound (128) according to amanner similar to Preparation 7 (5.43 g).

[0818]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.42 (3×3H, s), 3.72 (3H, s), 3.86(3H, s), 4.76 (2H, s), 6.61 (1H, d, J=16 Hz), 7.02 (1H, d, J=8.5 Hz),7.08-7.19 (2H, m), 7.25 (1H, dd, J=8.5, 2 Hz), 7.40-7.48 (2H, m),7.57-7.66 (2H, m), 8.71 (1H, s), 9.46 (1H, s);

[0819] MASS (ES+): m/e 457.

[0820] Preparation 130

[0821] Compound (130) was obtained from Compound (129) according to amanner similar to Preparation 8 (4.35 g).

[0822]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.72 (3H, s), 3.85 (3H, s), 5.67(2H, s), 6.65 (1H, d, J=16 Hz), 7.20-7.32 (2H, m), 7.49 (1H, s),7.54-7.62 (2H, m), 7.63 (1H, d, J=16 Hz), 7.80-7.88 (2H, m);

[0823] MASS (ES+): m/e 339.

[0824] Preparation 131

[0825] Compound (131) was obtained from Compound (130) according to amanner similar to Preparation. 12 (1.63 g).

[0826]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.83 (3H, s), 5.33 (2H, s), 6.47(1H, d, J=16 Hz), 7.14-7.26 (4H, m), 7.36 (1H, s), 7.50 (1H, m), 7.52(1H, d, J=16 Hz), 7.63 (1H, m), 12.70 (1H, s);

[0827] MASS (ES+): m/e 325.

[0828] Preparation 132

[0829] Compound (132) was obtained from Compound (131) according to amanner similar to Preparation 9 (1.93 g). The Compound (132) was used inExample 40.

[0830]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.77 (6H, m), 3.53 (1H, m),3.82 (3H, s), 3.95 (1H, m), 4.90 (1H, m), 5.32 (2H, s), 6.41 (1H, d,J=16 Hz), 7.10-7.28 (5H, m), 7.43 (1H, d, J=16 Hz), 7.50 (1H, m), 7.62(1H, m), 11.13 (1H, s), 12.69 (1H, s);

[0831] MASS (ES+): m/e 424.

[0832] Preparation 133

[0833] Compound (133) was obtained from Compound (86) according to amanner similar to Preparation 113 (437 mg).

[0834]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7 Hz), 2.92 (2×3H, s),4.21 (2H, s), 4.26 (2H, q, J=7 Hz), 6.39 (1H, d, J=16 Hz), 6.75-6.84(2H, m), 7.24-7.32 (2H, m), 7.42-7.50 (3H, m), 7.63 (1H, d, J=16 Hz);

[0835] MASS (ES+): m/e 350.

[0836] Preparation 134

[0837] The ethylcarbonyl group of Compound (133) was deprotectedaccording to a manner similar to Preparation 12. The obtained compound(300 mg) was suspended in dioxane (10 mL). To the suspension was added1N-NaOH (3 mL) di-tert-butyldicarbonate (407 mg) in dioxane (4 mL) andthe mixture was stirred at ambient temperature for 12 hours. Additionaldi-tert-butyldicarbonate (407 mg) and 1N-NaOH (3 mL) was added and themixture was stirred at ambient temperature for 6 hours. The solvent wasevaporated in vacuo and the residue was partioned between diisopropylether and water. The aqueous phase was acidified with hydrochloric acidto pH 5 and the precipitate was collected and washed with water to giveCompound (134) (326 mg) as a pale brown powder. The obtained compound(134) was used in Example 41.

[0838]¹H-NMR (300 MHz, CDCl₃, δ): 1.45-1.95 (15H, m), 2.94-3.03 (6H, m),3.65 (1H, m), 3.96 (1H, m), 4.54-4.64 (2H, m), 5.00 (1H, m), 6.30-7.80(9H, m);

[0839] MASS (ES+) m/e 521.

[0840] Preparation 135

[0841] Compound (135) was obtained according to a manner similar toPreparation 106 (2.11 g).

[0842]¹H-NMR (300 MHz, CDCl₃, δ): 3.79 (3H, s), 3.93 (3H, s), 6.30 (1H,d, J=16 Hz), 6.85 (1H, d, J=8 Hz), 7.03 (1H, dd, J=8, 2 Hz), 7.14 (1H,d, J=2 Hz), 7.60 (1H, d, J=16 Hz);

[0843] MASS (ES+): m/e 209.

[0844] Preparation 136

[0845] Compound (136) was obtained from Compound (135) according to amanner similar to Preparation 107 (3.12 g).

[0846]¹H-NMR (300 MHz, CDCl₃, δ): 1.48 (3×3H, s), 3.79 (3H, s), 3.91(3H, s), 4.61 (2H, s), 6.26 (1H, d, J=16 Hz), 6.89 (1H, d, J=8.3 Hz),6.97 (1H, d, J=2 Hz), 7.14 (1H, dd, J=8.3, 2 Hz), 7.60 (1H, d, J=16 Hz);

[0847] MASS (ES+): m/e 323.

[0848] Preparation 137

[0849] Compound (137) was obtained from Compound (136) according to amanner similar to Preparation 8 (2.03 g).

[0850]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.71 (3H, s), 3.81 (3H, s), 4.75(2H, s), 6.54 (1H, d, J=16 Hz), 7.01 (1H, d, J=8 Hz), 7.27 (1H, dd, J=8,2 Hz), 7.31 (1H, d, J=2 Hz), 7.57 (1H, d, J=16 Hz), 12.87 (1H, br);

[0851] MASS (ES+): m/e 267.

[0852] Preparation 138

[0853] Compound (138) was obtained from Compound (137) according to amanner similar to Preparation 8 (2.97 g).

[0854]¹H-NMR (300 MHz, CDCl₃, δ): 1.47 (3×3H, s), 3.80 (3H, s), 3.93(3H, s), 4.72 (2H, s), 6.33 (1H, d, J=16 Hz), 6.95 (1H, d, J=8 Hz), 6.96(1H, br), 7.12-7.29 (4H, m), 7.47 (1H, br-d, J=7.5 Hz), 7.62 (1H, d,J=16 Hz), 7.64 (1H, br-d, J=7.5 Hz), 9.02 (1H, s);

[0855] MASS (ES+) m/e 457.

[0856] Preparation 139

[0857] Compound (139) was obtained from Compound (138) according to amanner similar to Preparation 7 (2.29 g).

[0858]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.71 (3H, s), 3.83 (3H, s), 5.63(2H, s), 6.61 (1H, d, J=16 Hz), 7.11 (1H, d, J=8.4 Hz), 7.42 (1H, dd,J=8.4, 2 Hz), 7.50-7.58 (2H, m), 7.61 (1H, d, J=16 Hz), 7.65 (1H, d, J=2Hz), 7.78-7.96 (2H, m);

[0859] MASS (ES+) m/e 339.

[0860] Preparation 140

[0861] Compound (140) was obtained from Compound (139) according to amanner similar to Preparation 12 (1.84 g).

[0862]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.81 (3H, s), 5.36 (2H, s), 6.45(1H, d, J=16 Hz), 7.04 (1H, d, J=8.8 Hz), 7.20-7.28 (2H, m), 7.28 (1H,dd, J=8.8, 2 Hz), 7.52 (1H, d, J=16 Hz), 7.55-7.64 (2H, m), 7.57 (1H, d,J=2 Hz), 12.26 (1H, br-s);

[0863] MASS (ES+) m/e 325.

[0864] Preparation 141

[0865] Compound (141) was obtained from Compound (140) according to amanner similar to Preparation 9 (609 mg). The Compound (141) was used inExample 42.

[0866]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.42-1.78 (6H, m), 3.53 (1H, m) 3.81(3H, s), 3.96 (1H, m), 4.90 (1H, m), 5.32 (2H, s), 6.40 (1H, br-d, J=16Hz), 7.05 (1H, d, J=8.4 Hz), 7.16-7.26 (3H, m), 7.36-7.47 (2H, m),7.50-7.66 (2H, m), 11.18 (1H, br), 12.69 (1H, br);

[0867] MASS (ES+) m/e 424.

[0868] Preparation 142

[0869] Compound (142) was obtained from Compound (6) according to amanner similar to Preparation 7 (400 mg).

[0870]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.76 (2H, s), 5.86 (2H,s), 6.33 (1H, s), 6.38 (1H, d, J=16.1 Hz), 6.77 (1H, s), 7.37 (2H, d,J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz), 7.58 (1H, d, J=16.5 Hz);

[0871] MASS (ES+): m/e 397 (M+1).

[0872] Preparation 143

[0873] Compound (143) was obtained from Compound (142) according to amanner similar to Preparation 8 (305 mg).

[0874]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.44 (2H, s); 6.15 (2H, s), 6.55(1H, d, J=16.2 Hz), 7.29 (2H, s), 7.42 (2H, d, J=8.1 Hz), 7.58 (1H, d,J=15.7 Hz), 7.72 (2H, d, J=8.4 Hz);

[0875] MASS (ES+): m/e 323 (M+1).

[0876] Preparation 144

[0877] Compound (144) was obtained from Compound (143) according to amanner similar to Preparation 9 (196 mg). The Compound (144) was used inExample 43.

[0878]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 3.53(1H, m), 3.95 (1H, m), 4.11 (2H, s), 4.90 (1H, s), 5.95 (2H, s), 6.46(1H, d, J=15.4 Hz), 6.96 (1H, s), 7.03 (1H, s), 7.34 (2H, d, J=8.1 Hz),7.46 (1H, d, J=15.8 Hz), 7.52 (2H, d, J=8.1 Hz);

[0879] MASS (ES+): m/e 422 (M+1).

[0880] Preparation 145

[0881] Compound (145) was obtained from Compound (6) according to amanner similar to Preparation 7 (460 mg).

[0882]¹H-NMR (300 MHz, CDCl₃, δ): (1:1 mixture) 1.54 (9H, s), 3.71 (3H,s), 3.82 (2H, s), 6.30 (1H, d, J=8.1 Hz), 6.39 (1H, d, J=16.1 Hz), 6.41(1H, d, J=8.0 Hz), 6.98 (1H, t, J=8.4 Hz), 7.40 (2H, d, J=8.4 Hz), 7.54(2H, d, J=8.4 Hz), 7.59 (1H, d, J=15.7 Hz), 1.54 (9H, s), 3.77 (2H, s),3.83 (3H, s), 6.37 (1H, d, J=15.8 Hz), 6.65-6.74 (sH, m), 6.80 (1H, dd,J=7.7, 1.8 Hz), 7.37 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 7.57(1H, d, J=17.2 Hz);

[0883] MASS (ES+): m/e 383 (M+1).

[0884] Preparation 146

[0885] Compound (146) was obtained from Compound (145) according to amanner similar to Preparation 8 (326 mg).

[0886]¹H-NMR (300 MHz, DMSO-d, 6): 4.00 (3H, s), 4.44 (2H, s), 6.54 (1H,d, J=15.7 Hz), 7.06 (1H, d, J=8.7 Hz), 7.24 (1H, d, J=8.1 Hz), 7.40 (1H,t, J=8.1 Hz), 7.44 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=16.0 Hz), 7.71 (2H,d, J=8.2 Hz);

[0887] MASS (ES+): m/e 309 (M+1).

[0888] Preparation 147

[0889] Compound (147) was obtained from Compound (146) according to amanner similar to Preparation 9 (308 mg). The Compound (147) was used inExample 44.

[0890]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (3H, br), 1.69 (3H, br), 3.52(1H, m), 3.90 (3H, s), 3.95 (1H, m), 4.15 (2H, s), 4.90 (1H, s), 6.46(1H, d, J=16.2 Hz), 6.68 (1H, br), 7.04 (2H, m), 7.35 (2H, d, J=8.0 Hz),7.45 (1H, d, J=16.4 Hz), 7.52 (2H, d, J=8.0 Hz);

[0891] MASS (ES+): m/e 408 (M+1).

[0892] Preparation 148

[0893] Compound (148) was obtained according to a manner similar toPreparation 6 (929 mg).

[0894]¹H-NMR (300 MHz, CDCl₃, δ): 1.50 (3H, d, J=6.9-Hz); 1.53 (9H, s),3.75 (1H, q, J=7.1 Hz), 6.33 (1H, d, J=16.1 Hz), 7.32 (2H, d, J=8.5 Hz),7.45 (2H, d, J=8.1 Hz), 7.55 (1H, d, J=16.1 Hz);

[0895] MASS (ES+): not detected.

[0896] Preparation 149

[0897] Compound (149) was obtained from Compound (148) according to amanner similar to Preparation 7 (1.09 g).

[0898]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 1.60 (3H, d, J=7.0 Hz),3.79 (1H, q, J=7.0 Hz), 6.36 (1H, d, J=16.0 Hz), 6.70-6.78 (2H, m),6.98-7.04 (1H, m), 7.08-7.15 (1H, m), 7.40 (2H, d, J=8.6 Hz), 7.51 (2H,d, J=8.4 Hz), 7.56 (1H, d, J=16.0 Hz);

[0899] MASS (ES+): m/e 367 (M+1).

[0900] Preparation 150

[0901] Compound (150) was obtained from Compound (149) according to amanner similar to Preparation 8 (567 mg).

[0902]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.86 (3H, d, J=7.0 Hz), 4.83 (1H, q,J=7.0 Hz), 6.55 (1H, d, J=15.8 Hz), 7.49 (2H, d, J=8.1 Hz), 7.52-7.55(2H, m), 7.58 (1H, d, J=16.4 Hz), 7.73 (2H, d, J=8.1 Hz), 7.76-7.79 (2H,m);

[0903] MASS (ES+): m/e 293 (M+1).

[0904] Preparation 151

[0905] Compound (151) was obtained from Compound (150) according to amanner similar to Preparation 9 (598 mg). The Compound (151) was used inExample 45.

[0906]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.68 (3H, br), 1.70(3H, d, J=7.3 Hz), 3.52 (1H, m), 3.93 (1H, m), 4.41 (1H, q, J=7.0 Hz),4.89 (1H, s), 6.47 (1H, d, J=16.5 Hz), 7.08-7.15 (2H, m), 7.34-7.40 (2H,m), 7.37 (2H, d, J=8.3 Hz), 7.44 (1H, d, J=16.5 Hz), 7.52 (2H, d, J=8.0Hz);

[0907] MASS (ES+): m/e 392 (M+1).

[0908] Preparation 152

[0909] Compound (152) was obtained according to a manner similar toPreparation 6 (1.2 g).

[0910]¹H-NMR (300 MHz, CDCl₃, δ): 1.51 (3H, d, J=6.9 Hz), 1.53 (9H, s),3.76 (1H, q, J=7.1 Hz), 6.34 (1H, d, J=16.0 Hz), 7.33 (2H, d, J=8.5 Hz),7.47 (2H, d, J=81 Hz), 7.56 (1H, d, J=16.0 Hz);

[0911] MASS (ES+): not detected.

[0912] Preparation 153

[0913] Compound (153) was obtained from Compound (152) according to amanner similar to Preparation 7 (1.298 g).

[0914]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 1.61 (3H, d, J=7.0 Hz),3.79 (1H, q, J=7.0 Hz), 6.36 (1H, d, J=16.0 Hz), 6.70-6.75 (2H, m),6.97-7.05 (1H, m), 7.09-7.14 (1H, m), 7.24 (2H, d, J=8.4 Hz), 7.51 (2H,d, J=8.5 Hz), 7.56 (1H, d, J=16.2 Hz);

[0915] MASS (ES+): m/e 367 (M+1)

[0916] Preparation 154

[0917] Compound (154) was obtained from Compound (153) according to amanner similar to Preparation 8 (611 mg).

[0918]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.86 (3H, d, J=7.4 Hz), 4.83 (1H, q,J=7.1 Hz), 6.55 (1H, d, J=15.7 Hz), 7.49 (2H, d, J=8.0 Hz), 7.52-7.55(2H, m), 7.58 (1H, d, J=16.2 Hz), 7.74 (2H, d, J=8.4 Hz), 7.76-7.79 (2H,m);

[0919] MASS (ES+): m/e 293 (M+1).

[0920] Preparation 155

[0921] Compound (155) was obtained from Compound (154) according to amanner similar to Preparation 9 (700 mg). The Compound (155) was used inExample 46.

[0922]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.52 (3H, br), 1.68 (3H, br), 1.70(3H, d, J=6.9 Hz), 3.50 (1H, m), 3.93 (1H, m), 4.41 (1H, q, J=7.1 Hz),4.89 (1H, s), 6.48 (1H, d, J=16.1 Hz), 7.08-7.14 (2H, m), 7.34-7.40 (2H,m), 7.37 (2H, d, J=8.3 Hz), 7.47 (2H, d, J=16.1 Hz), 7.51 (2H, d, J=8.9Hz);

[0923] MASS (ES+): m/e 392 (M+1).

[0924] Preparation 156

[0925] Compound (156) was obtained according to a manner similar toPreparation 7 (536 mg).

[0926]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7.0 Hz), 1.46 (9H, s),1.48 (9H, s), 4.05 (2H, q, J=7.0 Hz), 6.50 (1H, d, J=16.1 Hz), 6.98 (2H,d, J=8.4 Hz), 7.01 (1H, d, J=7.7 Hz), 7.40 (2H, d, J=7.7 Hz), 7.50 (2H,d, J=8.8 Hz), 7.52 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=16.3 Hz), 7.66 (2H,d, J=8.1 Hz), 7.68 (1H, s);

[0927] MASS (ES+): m/e 573 (M+1).

[0928] Preparation 157

[0929] Compound (157) was obtained from Compound (156) according to amanner similar to Preparation 8 (345 mg).

[0930]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.36 (3H, t, J=7.0 Hz), 4.08 (2H, q,J=7.0 Hz), 4.55 (2H, s), 6.56 (1H, d, J=16.1 Hz), 7.05 (2H, d, J=8.8Hz), 7.49 (2H, d, J=8.4 Hz), 7.60 (1H, d, J=16.1 Hz), 7.65 (2H, d, J=9.1Hz), 7.74 (2H, d, J=8.4 Hz), 7.77 (2H, m), 7.88 (1H, s);

[0931] MASS (ES+): m/e 399 (M+1).

[0932] Preparation 158

[0933] Compound (158) was obtained from Compound (157) according to amanner similar to Preparation 9 (370 mg). The Compound (158) was used inExample 47.

[0934]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.35 (3H, t, J=7.0 Hz), 1.54 (3H,br), 1.68 (3H, br), 3.53 (1H, m), 3.94 (1H, m), 4-0.06 (2H, q, J=7.0Hz), 4.21 (2H, s), 4.90 (1H, s), 6.48 (1H, d, J=16.1 Hz), 7.00 (2H, dd,J=8.8, 2.2 Hz), 7.38 (3H, m), 7.44 (1H, s), 7.50 (1H, m), 7.53-7.60 (5H,m), 7.72 (1H, s);

[0935] MASS (ES+): m/e 498 (M+1).

[0936] Preparation 159

[0937] Compound (159) was obtained from Compound (6) according to amanner similar to Preparation 7 (652 mg).

[0938]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47 (9H, s), 1.49 (9H, s), 3.77(2H, s), 6.50 (1H, d, J=16.1 Hz), 7.40 (2H, d, J=7.9 Hz), 7.49 (1H, d,J=7.9 Hz), 7.50 (1H, m), 7.60 (1H, m), 7.67 (2H, d, J=8.1 Hz), 8.00 (1H,m), 8.51 (1H, m), 8.55 (1H, m), 8.83 (1H, m), 9.76 (1H, d, J=7.7 Hz);

[0939] MASS (ES+): m/e 530 (M+1).

[0940] Preparation 160

[0941] Compound (160) was obtained from Compound (159) according to amanner similar to Preparation 8 (458 mg).

[0942]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.56 (1H, d, J=16.1Hz), 7.51 (2H, d, J=8.1 Hz), 7.59 (1H, d, J=16.1 Hz), 7.74 (2H, d, J=8.4Hz), 7.90 (2H, s), 8.14 (1H, s), 8.53 (1H, d, J=7.7 Hz), 8.76 (1H, d,J=5.1 Hz), 9.15 (1H, s);

[0943] MASS (ES+): m/e 356 (M+1).

[0944] Preparation 161

[0945] Compound (161) was obtained from Compound (160) according to amanner similar to Preparation 9 (316 mg). The Compound (161) was used inExample 48.

[0946]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 3.53(1H, m), 3.95 (1H, m), 4.23 (2H, s), 4.90 (1H, s), 6.48 (1H, d, J=15.7Hz), 7.39 (2H, d, J=8.1 Hz), 7.44-7.52 (4H, m), 7.54 (2H, d, J=8.4 Hz),7.80 (1H, br), 8.08 (1H, m), 8.53 (1H, m), 8.90 (1H, m);

[0947] MASS (ES+): m/e 455 (M+1).

[0948] Preparation 162

[0949] Compound (162) was obtained according to a manner similar toPreparation 7 (748 mg).

[0950]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.80 (2H, s), 6.38 (1H,d, J=16.1 Hz), 6.76 (1H, d, J=8.1 Hz), 7.11 (sH,), 7.38 (2H, d, J=7.7Hz), 7.47 (2H, d, J=7.7 Hz), 7.52-7.60 (5H, m), 7.71 (2H, d, J=7.0 Hz);

[0951] MASS (ES+): m/e 457 (M+1).

[0952] Preparation 163

[0953] Compound (163) was obtained from Compound (162) according to amanner similar to Preparation 8 (521 mg).

[0954]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.49 (2H, s), 6.54 (1H, d, J=16.1Hz), 7.47 (2H, d, J=7.7 Hz), 7.56-7.62 (3H, m), 7.67-7.77 (3H, m), 7.81(2H, s), 7.98 (1H, s);

[0955] MASS (ES+): m/e 383 (M+1)

[0956] Preparation 164

[0957] Compound (164) was obtained from Compound (163) according to amanner similar to Preparation 9 (185 mg). The Compound (164) was used inExample 49.

[0958]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 3.53(1H, m), 3.95 (1H, m), 4.27 (2H, s), 4.90 (1H, s), 6.48 (1H, d, J=16.1Hz), 7.39 (2H, d, J=8.0 Hz), 7.46 (1H, d, J=15.7 Hz), 7.56 (5H, m), 7.62(2H, s), 7.67 (3H, m), 7.73 (2H, d, J=7.0 Hz), 7.86

[0959] (1H, s)

[0960] MASS (ES+): m/e 482 (M+1).

[0961] Preparation 165

[0962] To a solution of Compound (60) in EtOH (3 mL) was added sodiumborohydride (28 mg) at 5° C. and the mixture was allowed to warm toambient temperature. After stirred for 0.5 hr, sodium borohydride (14mg) was added to the mixture, and sodium borohydride (14 mg) was thenadditionally added three times to the mixture before Compound (60) wasdisappeared. The mixture was poured into water and washed with ether.The aqueous phase was acidified with 1N hydrochloric acid to pH 4 andextracted with ethyl acetate, washed with brine. The organic phase wasdried over Na₂SO₄ and the solvent was removed in vacuo to give Compound(165) (120 mg) as colorless form.

[0963]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.44 (2H, s), 5.86 (1H, s), 6.06(1H, br), 6.53 (1H, d, J=16.1 Hz), 7.19 (1H, t, J=7.3 Hz), 7.29 (2H, t,J=7.3 Hz), 7.38 (3H, d, J=7.0 Hz), 7.42 (2H, d, J=8.1 Hz), 7.56 (1H, d,J=5.5 Hz), 7.60 (1H, d, J=1.8 Hz), 7.67 (1H, s), 7.70 (2H, d, J=8.4 Hz);

[0964] MASS (ES+): m/e 385 (M+1).

[0965] Preparation 166

[0966] Compound (166) was obtained from Compound (165) according to amanner similar to Preparation 9 (104 mg). The Compound (166) was used inExample 50.

[0967]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.68 (3H, br), 3.50(1H, m), 3.93 (1H, m), 4.16 (2H, s), 4.90 (1H, s), 5.77 (1H, s), 5.82(1H, br), 6.45 (1H, d, J=16.5 Hz), 7.12 (1H, m), 7.18 (1H, d, J=6.6 Hz),7.27 (2H, d, J=7.5 Hz), 7.32 (2H, t, J=7.3 Hz), 7.34 (1H, s), 7.36 (2H,d, J=7.4 Hz), 7.42 (2H, m), 7.51 (2H, d, J=8.1 Hz)

[0968] MASS (ES+): m/e 484 (M+1).

[0969] Preparation 167

[0970] Compound (167) was obtained from Compound (6) according to amanner similar to Preparation 7 (234 mg).

[0971]¹H-NMR (300 MHz, CDCl₃, δ): 2.96 (3H, s), 2.98 (3H, s), 3.80 (2H,s), 6.38 (1H, d, J=16.8 Hz), 6.75 (2H, d, J=8.5 Hz), 6.95 (1H, s), 6.99(1H, d, J=7.3 Hz), 7.14 (1H, d, J=7.3 Hz), 7.40 (2H, d, J=7.0 Hz), 7.43(2H, d, J=7.0 Hz), 7.54 (2H, d, J=7.3 Hz), 7.59 (1H, d, J=15.0 Hz);

[0972] MASS (ES+): m/e 472 (M+1).

[0973] Preparation 168

[0974] Compound (168) was obtained from Compound (167) according to amanner similar to Preparation 8 (263 mg).

[0975]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.04 (6H, s), 4.60 (2H, s), 6.57(1H, d, J=16.1 Hz), 7.42 (1H, d, J=8.1 Hz), 7.60 (1H, d, J=16.1 Hz),7.61-7.72 (2H, m), 7.74 (2H, d, J=8.4 Hz), 7.80 (2H, s), 7.90 (1H, s);

[0976] MASS (ES+): m/e 398 (M+1).

[0977] Preparation 169

[0978] Compound (169) was obtained from Compound (168) according to amanner similar to Preparation 9 (116 mg). The Compound (169) was used inExample 51.

[0979]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br), 1.69 (3H, br), 2.93(6H, s), 3.53 (1H, m), 3.94 (1H, m), 4.20 (2H, s), 4.90 (1H, s), 6.47(1H, d, J=15.8 Hz), 6.81 (2H, d, J=9.1 Hz), 7.38 (4H, d, J=8.4 Hz), 7.43(1H, m), 7.50 (2H, m), 7.54 (2H, d, J=8.4 Hz), 7.69 (1H, s);

[0980] MASS (ES+): m/e 497 (M+1).

[0981] Preparation 170

[0982] Compound (170) was obtained from Compound (6) according to amanner similar to Preparation 7 (334 mg).

[0983]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.81 (2H, s), 4.02 (2H,br), 6.39 (1H, d, J=16.1 Hz), 7.03 (1H, br), 7.29 (1H, br), 7.38 (2H, d,J=8.0 Hz), 7.44 (1H, br), 7.55 (2H, dd, J=8.0 Hz), 7.58 (1H, d, J=16.2Hz);

[0984] MASS (ES+): m/e 421 (M+1)

[0985] Preparation 171

[0986] Compound (171) was obtained from Compound (170) according to amanner similar to Preparation 8 (247 mg).

[0987]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.39. (2H, s), 6.52 (1H, d, J=15.6Hz), 7.42 (2H, d, J=7.7 Hz), 7.58 (1H, d, J=15.8 Hz), 7.61 (1H, d, J=8.8Hz), 7.69 (2H, d, J-8.1 Hz), 7.79 (1H, d, J=9.5 Hz), 7.97 (1H, s);

[0988] MASS (ES+): m/e 347 (M+1).

[0989] Preparation 172

[0990] Compound (172) was obtained from Compound (171) according to amanner similar to Preparation 9 (308 mg). The Compound (172) was used inExample 52.

[0991]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.76 (3H, br), 3.52(1H, m), 3.96 (1H, m), 4.27 (2H, s), 4.90 (1H, s), 6.48 (1H, d, J=16.4Hz), 7.38 (2H, d, J=8.5 Hz), 7.46 (1H, d, J=8.4 Hz), 7.47 (1H, d, J=16.0Hz), 7.55 (2H, d, J=7.9 Hz), 7.69 (1H, d, J=8.1 Hz), 7.85 (1H, s);

[0992] MASS (ES+): m/e 346 (M+1).

[0993] Preparation 173

[0994] Compound (173) was obtained from Compound (6) according to amanner similar to Preparation 7 (617 mg).

[0995]¹H-NMR (300 MHz, CDCl₃, δ): 1.48 (9H, s), 3.69 (2H, s), 5.25 (2H,br), 6.50 (1H, d, J=15.7 Hz), 6.49-6.55 (1H, m), 6.95-7.00 (1H, m), 7.37(2H, d, J=8.1 Hz), 7.54 (1H, d, J=16.1 Hz), 7.65 (2H, d, J=8.4 Hz);

[0996] MASS (ES+): m/e 389 (M+1).

[0997] Preparation 174

[0998] Compound (174) was obtained from Compound (173) according to amanner similar to Preparation 8 (466 mg).

[0999]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.36 (2H, s), 6.52 (1H, d, J=16.1Hz), 7.31-7.40 (2H, m), 7.43 (2H, d, J=8.1 Hz), 7.57 (1H, d, J=15.7 Hz),7.69 (2H, d, J=8.1 Hz);

[1000] MASS (ES+): m/e 315 (M+1).

[1001] Preparation 175

[1002] Compound (175) was obtained from Compound (174) according to amanner similar to Preparation 9 (542 mg). The Compound (175) was used inExample 53.

[1003]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 3.52(1H, m), 3.96 (1H, m), 4.22 (2H, s), 4.90 (1H, s), 6.47 (1H, d, J=16.1Hz), 7.13-7.22 (2H, m), 7.37 (2H, d, J=8.0 Hz), 7.47 (1H, d, J=15.7 Hz),7.54 (2H, d, J=8.0 Hz);

[1004] MASS (ES+): m/e 414 (M+1).

[1005] Preparation 176

[1006] Compound (176) was obtained from Compound (6) according to amanner similar to Preparation 7 (555 mg).

[1007]¹H-NMR (300 MHz, CDCl₃, δ): 0.93 (6H, d, J=6.6 Hz), 1.54 (9H, s),1.62 (2H, dt, J=7.0, 7.0 Hz), 1.79 (1H, hept, J=6.8 Hz), 3.76 (2H, s),3.90 (2H, t, J=6.5 Hz), 6.30 (2H, m), 6.38 (1H, d, J=16.1 Hz), 6.91 (1H,d, J=9.5 Hz), 7.53 (2H, d, J=8.7 Hz), 7.55 (1H, d, J=16.6 Hz);

[1008] MASS (ES+): m/e 439 (M+1).

[1009] Preparation 177

[1010] Compound (177) was obtained from Compound (176) according to amanner similar to Preparation 8 (398 mg).

[1011]¹H-NMR (300 MHz, DMSO-d₆, δ): 0.94 (6H, d, J=6.7 Hz), 1.64 (2H,dt, J=6.7, 6.7 Hz), 1.79 (1H, hept, J=6.7 Hz), 4.07 (2H, t, J=6.7 Hz),4.50 (2H, s), 6.55 (1H, d, J=16.3 Hz), 7.10 (1H, dd, J=8.4, 2.2 Hz),7.21 (1H, d, J=2.2 Hz), 7.46 (2H, d, J=8.4 Hz), 7.59 (1H, d, J=16.1 Hz),7.62 (1H, d, J=8.7 Hz), 7.73 (2H, d, J=8.6 Hz);

[1012] MASS (ES+): m/e 365 (M+1).

[1013] Preparation 178

[1014] Compound (178) was obtained from Compound (177) according to amanner similar to Preparation 9 (176 mg). The Compound (178) was used inExample 54.

[1015]¹H-NMR (300 MHz, CDCl₃, δ): 0.92 (6H, d, J=6.7 Hz), 1.42-1.87 (6H,m), 1.64 (2H, dt, J=6.7 Hz), 1.80 (1H, hept, J=6.7 Hz), 3.52 (1H, m),3.94 (2H, t, J=6.7 Hz), 3.97 (1H, m), 4.11 (2H, s), 5.13 (1H, s), 6.18(1H, br.s), 6.84 (1H, dd, J=8.8, 2.5 Hz), 6.90 (4H, br.s), 7.04 (1H,br.s), 7.29 (1H, br.d), 7.45 (1H, d, J=8.8 Hz);

[1016] MASS (ES+): m/e 464 (M+1).

[1017] Preparation 179

[1018] Compound (179) was obtained from Compound (6) according to amanner similar to Preparation 7 (414 mg).

[1019]¹H-NMR (300 MHz, CDCl₃, δ): 1.28 (6H, d, J=6.3 Hz), 3.76 (2H, s),4.44 (1H, hept, J=6.3 Hz), 6.28 (2H, m), 6.37 (1H, d, J=15.8 Hz), 6.91(1H, d, J=9.0 Hz), 7.37 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz), 7.57(1H, d, J=15.7 Hz);

[1020] MASS (ES+): m/e 411 (M+1).

[1021] Preparation 180

[1022] Compound (180) was obtained from Compound (179) according to amanner similar to Preparation 8 (330 mg).

[1023]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.29 (6H, d, J=6.1 Hz), 4.69 (1H,hept, J=6.1 Hz), 6.55 (1H, d, J=16.2 Hz), 7.08 (1H, dd, J=2.6, 9.2 Hz),7.19 (1H, d, J=2.6 Hz), 7.59 (1H, d, J=16.1 Hz), 7.62 (1H, d, J=9.2 Hz),7.73 (2H, d, J=8.2 Hz);

[1024] MASS (ES+): m/e 337 (M+1).

[1025] Preparation 181

[1026] Compound (181) was obtained from Compound (180) according to amanner similar to Preparation 9 (281 mg). The obtained Compound (181)was used in Example 55.

[1027]¹H-NMR (300 MHz, CDCl₃, δ): 1.31 (6H, d, J=6.0 Hz), 1.53 (3H, br),1.69 (3H, br), 3.64 (1H, m), 4.01 (1H, m), 4.22 (2H, s), 4.47 (1H, hept,J=6.0 Hz), 5.05 (1H, m), 6.30 (1H, br), 6.85 (1H, d, J=9.0 Hz), 7.00(1H, s), 707-7.20 (2H, br), 7.26-7.35 (1H, br), 7.42 (2H, d, J=8.8 Hz);

[1028] MASS (ES+): m/e 436 (M+1).

[1029] Preparation 182

[1030] Compound (182) was obtained from Compound (6) according to amanner similar to Preparation 7 (546 mg).

[1031]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.78 (2H, s), 6.38 (1H, d, J=16.1Hz), 6.40 (2H, m), 6.89 (1H, s), 7.00 (2H, m), 7.09 (1H, t, J=7.3 Hz),7.31 (2H, dd, J=8.7, 7.6 Hz), 7.38 (2H, d, J=8.5 Hz), 7.54 (2H, d, J=7.4Hz), 7.58 (1H, d, J=16.2 Hz);

[1032] MASS (ES+): m/e 445 (M+1).

[1033] Preparation 183

[1034] Compound (183) was obtained from Compound (182) according to amanner similar to Preparation 8 (417 mg).

[1035]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.52 (2H, s), 6.56 (1H, d, J=16.1Hz), 7.17 (1H, t, J=7.3 Hz), 7.21 (1H, dd, J=9.1, 2.3 Hz), 7.30 (1H, d,J=2.3 Hz), 7.41 (2H, t, J=8.1 Hz), 7.48 (2H, d, J=8.5 Hz), 7.59 (1H, d,J=16.3 Hz), 7.73 (2H, d, J=8.8 Hz), 7.76 (1H, d, J=9.1 Hz);

[1036] MASS (ES+): m/e 371 (M+1).

[1037] Preparation 184

[1038] Compound (184) was obtained from Compound (183) according to amanner similar to Preparation 9 (442 mg). The Compound (184) was used inExample 56.

[1039]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br), 1.69 (3H, br), 3.52(1H, m), 3.95 (1H, m), 4.19 (2H, s), 4.90 (1H, s), 6.47 (1H, d, J=16.5Hz), 6.88 (1H, m), 6.94 (2H, m), 7.06 (2H, m), 7.35 (2H, m), 7.37 (3H,m), 7.46 (1H, d, J=16.4 Hz), 7.54 (2H, m);

[1040] MASS (ES+): m/e 470 (M+1).

[1041] Preparation 185

[1042] Compound (185) was obtained from Compound (6) according to amanner similar to Preparation 7 (163 mg). 1-NMR (300 MHz, CDCl₃, δ):3.74 (3H, s), 3.78 (2H, s), 6.31 (2H, m), 6.38 (1H, d, J=16.1 Hz), 6.93(1H, d, J=10.0 Hz), 7.38 (2H, d, J=8.0 Hz), 7.54 (2H, d, J=8.4 Hz), 7.58(1H, d, J=16.1 Hz);

[1043] MASS (ES+): m/e 383 (M+1).

[1044] Preparation 186

[1045] Compound (186) was obtained from Compound (185) according to amanner similar to Preparation 8 (127 mg).

[1046]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.84 (3H, s), 4.52 (2H, s), 6.55(1H, d, J=16.1 Hz), 7.12 (1H, dd, J=8.8, 2.2 Hz), 7.20 (1H., d, J=2.6Hz), 7.47 (2H, d, J=8.1 Hz), 7.59 (1H, d, J=16.1 Hz), 7.65 (1H, d, J=9.2Hz), 7.73 (2H, d, J=8.1 Hz);

[1047] MASS (ES+): m/e 309 (M+1).

[1048] Preparation 187

[1049] Compound (187) was obtained from Compound (186) according to amanner similar to Preparation 9 (127 mg). The Compound (187) was used inExample 57.

[1050]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br), 1.69 (3H, br), 3.53(1H, m), 3.75 (3H, s), 3.95 (1H, m), 4.15 (2H, s), 6.48 (1H, d, J=15.7Hz), 6.75 (1H, dd, J=8.8, 2.6 Hz), 6.98 (1H, s), 7.35 (3H, d, J=8.4 Hz),7.46 (1H, d, J=15.7 Hz), 7.53 (2H, d, J=8.0 Hz);

[1051] MASS (ES+): m/e 408 (M+1).

[1052] Preparation 188

[1053] To a stirred solution of Compound (247) (described in Preparation247 below, 1.75 g) in dichloromethane (20 mL) was added trifluoroaceticacid (20 mL) and the resulting mixture was stirred at ambienttemperature for 3 hrs. The mixture was concentrated in vacuo and theresidue was dissolved in N,N-dimethylformamide (25 mL). To this solutionwere successively added 1-hydroxybenzotriazole (731 mg),O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (588 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (840 mg) in an ice bath,and the resulting mixture was stirred at ambient temperature. After 16hrs, additional 1-hydroxybenzotriazole (157 mg),O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (136 mg) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (180 mg) were added tothe mixture and the mixture was stirred for additional 4 hrs. Themixture was extracted with ethyl acetate (300 mL) and successivelywashed with 5% aqueous potassium hydrogen sulfate (100 mL), saturatedaqueous sodium bicarbonate (100 mL) and brine (100 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified by flash chromatography eluting with ethylacetate to afford Compound (188) (1.82 g) as a colorless amorphoussolid. The Compound (188) was used in Example 60.

[1054]¹H-NMR (300 MHz, CDCl₃, δ): 1.50-1.91 (6H, m), 3.58-3.71 (1H, m),3.82 (3H, s), 3.88-4.21 (1H, m), 4.87-5.09 (3H, m), 6.17-6.40 (1H, m),7.03-7.61 (5H, m), 7.74-7.87 (4H, m);

[1055] MASS (ES+): m/z 496 (M+1)

[1056] Preparation 189

[1057] Compound (189) was obtained from Compound (249) described lateraccording to a manner similar to Preparation 188 (142 mg). The Compound(189) was used in Example 64.

[1058]¹H-NMR (300 MHz, CDCl₃, δ): 1.46-1.92 (6H, m), 3.56-3.69 (1H, m),3.89-4.18 (2H, m), 4.96-5.12 (2H, m), 6.11-6.37 (1H, m), 7.00-7.36 (7H,m), 7.64 (2H, d, J=8.4 Hz);

[1059] MASS (ES+): m/z 438 (M+1)

[1060] Preparation 190

[1061] Compound (190) was obtained from Compound (250) described lateraccording to a manner similar to Preparation 188 (110 mg). The Compound(190) was used in Example 68.

[1062]¹H-NMR (300 MHz, CDCl₃, δ): 1.43-1.90 (6H, m), 3.58-3.71 (1H, m),3.91-4.12 (3H, m), 5.03 (1H, br.s), 5.95-6.21 (1H, m), 7.00-7.42 (9H,m), 7.67-7.76 (2H, m);

[1063] MASS (ES+): m/z 404 (M+1).

[1064] Preparation 191

[1065] Compound (191) was obtained from Compound (226) described lateraccording to a manner similar to Preparation 188 (78 mg). The Compound(191) was used in Example 69.

[1066]¹H-NMR (300 MHz, CDCl₃, δ): 1.41-2.05 (6H, m), 3.54-3.69 (1H, m),3.89-4.05 (3H, m), 4.93 (1H, br.s), 6.04-6.28 (1H, m), 6.95-7.53 (8H,m), 7.73 (2H, d, J=7.0 Hz);

[1067] MASS (ES+): m/z 438 (M+1).

[1068] Preparation 192

[1069] Compound (192) was obtained obtained from Compound (242)described later according to a manner similar to Preparation 188 (638mg). The Compound (192) was used in Example 86.

[1070]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.26 (3H, t, J=7.0 Hz), 1.54 (3H,br.), 1.69 (3H, br.), 3.53 (1H, m), 3.95 (1H, m), 4.07 (2H, s), 4.24(2H, q, J=7.0 Hz), 4.90 (1H, s), 6.46 (1H, d, J=16.1 Hz), 7.36 (5H, m),7.52 (3H, m), 7.85 (2H, d, J=7.3 Hz);

[1071] MASS (ES+): m/e 476 (M+1).

[1072] Preparation 193

[1073] To a stirred solution of Compound (326) (200 mg, described laterin Preparation 326) in N,N-dimethylformamide (2 mL) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (90 mg) and1-hydroxybenzotriazole (79 mg) at ambient temperature, and the resultingmixture was stirred at the same temperature for 2 hrs. To this mixturewas added 28% ammonium hydroxide solution in water (0.08 mL), and themixture was stirred at ambient temperature for 16 hrs. The mixture wasextracted with ethyl acetate (50 mL), and successively washed withsaturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by preparative thin-layerchromatography eluting with methanol-chloroform (10:90 v/v) to affordCompound (193) (141 mg) as a colorless amorphous solid. The Compound(193) was used in Example 61.

[1074]¹H-NMR (300 MHz, CDCl₃—CD₃OD (9:1 v/v), 6): 1.51-1.94 (6H, m),3.59-3.72 (3H, m), 3.95-4.12 (1H, m), 4.99 (2H, br.s), 6.23-6.47 (1H,m), 7.22-7.30 (2H, m), 7.32-7.47 (4H, m), 7.55-7.69 (4H, m);

[1075] MASS (ES+): m/z 447 (M+1).

[1076] Preparation 194

[1077] To a stirred solution of Compound (193) (138 mg) in pyridine (2mL) was added trifluoroacetic anhydride (84 mg) in an ice bath. Theresulting mixture was stirred at the same temperature for 2 hrs and thenallowed to warm to ambient temperature. After 2 hrs, additionaltrifluoroacetic anhydride (84 mg) was added to the reaction mixture atambient temperature, and the mixture was stirred at the same temperaturefor an hour. The mixture was concentrated in vacuo and the residue wasextracted with chloroform (50 mL), and successively washed withsaturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). Theorganic layer was dried over anhydrous sodium sulfate and evaporated.The residue was purified by preparative thin-layer chromatographyeluting with ethyl acetate to afford Compound (194) (55 mg) as acolorless amorphous solid. The Compound (194) was used in Example 62.

[1078]¹H-NMR (300 MHz, CDCl₃, δ): 1.32-2.01 (6H, m), 3.48-4.10 (3H, m)4.16 (2H, br.s), 4.86-5.06 (1H, m), 6.97-7.52 (8H, m), 7.81-7.92 (2H,m);

[1079] MASS (ES+): m/z 429 (M+1).

[1080] Preparation 195

[1081] To a stirred solution of Compound (6) (500 mg) inN,N-dimethylformamide (8 mL) were successively added2,2-diethoxyethanamine (305 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (439 mg)and 1-hydroxybenzotriazole (309 mg) in an ice bath, and the resultingsolution was stirred at the same temperature for 15 min. The mixture wasthen allowed to warm to ambient temperature and stirred at the sametemperature for 16 hrs. The mixture was extracted with ethyl acetate (50mL), and successively washed with 5% aqueous potassium sulfate (25 mL),saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). Theorganic layer was dried over anhydrous sodium sulfate and evaporated togive crude Compound (195) (861 mg) as a colorless oil, which was used inthe next step without further purification.

[1082]¹H-NMR (300 MHz, CDCl₃, δ): 1.13 (3H, t, J=7.3 Hz), 1.54 (9H, s),3.36 (2H, t, J=5.5 Hz), 3.40-3.52 (1H, m), 3.58 (2H, s), 3.59-3.70 (1H,m), 4.42 (1H, t, J=5.5 Hz), 5.62 (1H, br.s), 6.36 (1H, d, J=16.1 Hz),7.28 (2H, d, J=8.1 Hz), 7.49 (2H, d, J=8.1 Hz), 7.57 (1H, d, J=16.1 Hz);

[1083] MASS (ES+): m/z 378 (M+1)

[1084] Preparation 196

[1085] A mixture of Compound (195) (603 mg), ammonium acetate (616 mg)and acetic acid (1.9 g) in xylene (12 mL) was heated at 170° C. for fivedays, during which time additional same amounts of ammonium acetate andacetic acid were added to the mixture every 12 hrs. The mixture wasconcentrated in vacuo and extracted with chloroform (100 mL). Theorganic phase was successively washed with saturated aqueous sodiumbicarbonate (25 mL) and brine (25 mL). The organic layer was dried overanhydrous sodium sulfate and evaporated. The residue was triturated withacetonitrile to afford Compound (196) (200 mg) as a pale tan amorphoussolid.

[1086]¹H-NMR (300 MHz, CDCl₃, δ): 1.47 (9H, s), 3.98 (2H, s), 6.46 (1H,d, J=16.1 Hz), 6.78 (1H, br.s), 7.00 (1H, br.s), 7.25 (2H, d, J=8.1 Hz),7.51 (1H, d, J=16.1 Hz), 7.61 (2H, d, J=8.1 Hz);

[1087] MASS (ES+): m/z 285 (M+1).

[1088] Preparation 197

[1089] Compound (197) was obtained according to a manner similar toPreparation 188 (51 mg). The obtained Compound (197) was used in Example112.

[1090]¹H-NMR (300 MHz, CDCl₃, δ): 1.18-2.23 (6H, m), 3.48-4.20 (5H, m),5.02-5.12 (1H, m), 6.90-7.53 (7H, m);

[1091] MASS (ES+): m/z 328 (M+1)

[1092] Preparation 198

[1093] Compound (198) was obtained from Compound (242) described lateraccording to a manner similar to Preparation 188 (638 mg). The obtainedCompound (198) was used in Example 86.

[1094] (Compound (198) is the same compound as Compound (192).)

[1095]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.26 (3H, t, J=7.0 Hz), 1.54 (3H,br.), 1.69 (3H, br.), 3.53 (1H, m), 3.95 (1H, m), 4.07 (2H, s), 4.24(2H, q, J=7.0 Hz), 4.90 (1H, s), 6.46 (1H, d, J=16.1 Hz), 7.36 (5H, m),7.52 (3H, m), 7.85 (2H, d, J=7.3 Hz);

[1096] MASS (ES+): m/e 476 (M+1).

[1097] Preparation 199

[1098] A solution of Compound (248) (427 mg, described later inPreparation 248) in 1N-hydrogen chloride in acetic acid (10 mL) washeated at 60° C. for 2 hrs. The solvent was evaporated in vacuo, and theresidue was triturated with the mixture of ethyl acetate and acetic acid(10:1 (v/v)) to give Compound (199) (353 mg) as an off-white solid.

[1099]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.41 (2H, s), 6.55 (1H, d, J=16 Hz),7.39 (2×1H, dd, J=8.8, 8.8 Hz), 7.47 (2×1H, d, J=8.2 Hz), 7.58 (1H, d,J=16 Hz), 7.71 (2×1H, d, J=8.2 Hz), 7.91 (2×1H, dd, J=8.8, 5 Hz), 8.05(1H, s);

[1100] MASS (ES+): m/z 323.

[1101] Preparation 200

[1102] Compound (200) was obtained from Compound (207) described lateraccording to a manner similar to Preparation 199 (361 mg).

[1103]¹H-NMR. (300 MHz, DMSO-d₆, δ): 2.51 (3H, s), 2.53 (3H, s), 4.28(2H, s);

[1104] MASS (ES+): m/z 285.

[1105] Preparation 201

[1106] Compound (201) was obtained from Compound (206) described lateraccording to a manner similar to Preparation 199 (433 mg).

[1107]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.25 (3H, s), 4.31 (2H, s), 6.55(1H, d, J=16 Hz), 7.45 (2×1H, d, J=8 Hz), 7.54-7.63 (3H, m), 7.67-7.75(3H, m), 7.86 (2×1H, d, J=8 Hz);

[1108] MASS (ES+): m/z 347.

[1109] Preparation 202

[1110] Compound (202) was obtained from Compound (256) described lateraccording to a manner similar to Preparation 199 (181 mg).

[1111]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.65-1.79 (6H, m), 1.85-1.91 (6H,m), 2.00-2.07 (3H, m), 4.32 (2H, s), 6.54 (1H, d, J=16 Hz), 7.25 (1H,s), 7.40 (2H, d, J=8 Hz), 7.57 (1H, d, J=16 Hz), 7.70 (2H, d, J=8 Hz).

[1112] MASS (ES+): m/z 363 (M+1).

[1113] Preparation 203

[1114] To a stirred solution of Compound (199) (316 mg) inN,N-dimethylformamide (5 mL) were addedO-(tetrahydro-2H-pyran-2-yl)hydroxylamine (206 mg),1-hydroxybenzotriazole (238 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (338 mg),and the resulting mixture was stirred at ambient temperature for 5 hrs.The reaction mixture was diluted with ethyl acetate and washedsuccessively with water, saturated sodium hydrogen carbonate solutionand brine. The organic phase was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by preparativethin-layer chromatography (chloroform:methanol=10:1) to give Compound(203) (341 mg) as a pale yellow powder.

[1115]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.45-1.75 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.03 (2H, m), 4.90 (1H, m), 6.46 (1H, d, J=16 Hz), 7.14(2×1H, dd, J=8.8, 8.8 Hz), 7.32 (2×1H, d, J=8.5 Hz), 7.42-7.57 (4H, m),7.76 (2×1H, dd, J=8.8, 6.0 Hz), 11.22 (1H, s), 11.98 (1H, br-s);

[1116] MASS (ES+): m/z 422.

[1117] Preparation 204

[1118] To a suspension of p-iodo-phenylalanine (1.20 g) in n-BuOH (15mL) was added 1-phenyl-1,2,3-butanetrione-2-oxime (788 mg). Theresulting mixture was refluxed for 2 days and cooled, then concentratedin vacuo. The residue was triturated with ethyl acetate to give Compound(204) (870 mg) as a pale yellow solid.

[1119]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.48 (3H, s), 3.96 (2H, s), 7.08(2×1H, d, J=8.5 Hz), 7.44-7.60 (3H, m), 7.67 (2×1H, d, J=8.5 Hz), 8.18(2×1H, d, J=8 Hz), 12.44 (1H, s);

[1120] MASS (ES+): m/z 403.

[1121] Preparation 205

[1122] Compound (205) was obtained from p-iodophenylalanine according toa manner similar to Preparation 204 (402 mg).

[1123]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.35 (3H, s), 2.38 (3H, s), 3.91(2H, s), 7.07 (2×1H, d, J=8 Hz), 7.67 (2×1H, d, J=8 Hz);

[1124] MASS (ES+): m/z 341.

[1125] Preparation 206

[1126] To a stirred solution of Compound (204) (661 mg) in DMF (10 mL)were added tert-butyl acrylate (0.72 mL), palladium(II) acetate (18 mg),tris(2-methylphenyl)phosphine (100 mg) and N,N-diisopropylethylamine(0.86 mL). The mixture was stirred at 90° C. for 4 hrs. The resultingmixture was allowed to cool to ambient temperature, poured into waterand extracted with ethyl acetate. The organic phase was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (1:1 v/v) to give Compound (206) (707 mg) as apale yellow foam.

[1127]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47 (3×3H, s), 2.48 (3H, s), 4.02(2H, s), 6.48 (1H, d, J=16 Hz), 7.30 (2×1H, d, J=8.5 Hz), 7.44-7.58 (4H,m), 7.64 (2×1H, d, J=8.5 Hz), 8.19 (2×1H, d, J=7.5 Hz), 12.49 (1H, s);

[1128] MASS (ES+): m/z 403.

[1129] Preparation 207

[1130] Compound (207) was obtained from Compound (205) according to amanner similar to Preparation 206 (370 mg).

[1131]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (3×3H, s), 2.45 (3H, s), 2.54(3H, s), 4.08 (2H, s), 6.36 (1H, d, J=16 Hz), 7.25 (2×1H, d, J=8 Hz),7.48 (2×1H, d, J=8 Hz), 7.56 (1H, d, J=16 Hz);

[1132] MASS (ES+): m/z 341.

[1133] Preparation 208

[1134] Compound (208) was obtained from Compound (201) according to amanner similar to Preparation 188 (461 mg). The Compound (208) was usedin Example 66.

[1135]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.76 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.02 (2H, s), 4.90 (1H, m), 6.47 (1H, d, J=16 Hz), 7.31(2×1H, d, J=8.5 Hz), 7.42-7.68 (6H, m), 8.19 (2×1H, d, J=7 Hz), 11.22(1H, s), 11.48 (1H, s);

[1136] MASS (ES+): m/z 446.

[1137] Preparation 209

[1138] Compound (209) was obtained from Compound (200) according to amanner similar to Preparation 188 (268 mg). The Compound (209) was usedin Example 65.

[1139]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.46-1.78 (6H, m), 2.36 (3H, s),2.39 (3H, s), 3.53 (1H, m), 3.96 (1H, m), 3.97 (2H, s), 4.90 (1H, m),6.47 (1H, d, J=16 Hz), 7.29 (2×1H, d, J=8 Hz), 7.47 (1H, d, J=16 Hz),7.53 (2×1H, d, J=8 Hz), 11.2.2 (1H, s), 12.31 (1H, br-s);

[1140] MASS (ES+): m/z 384.

[1141] Preparation 210

[1142] Compound (210) was obtained from Compound (340) described lateraccording to a manner similar to Preparation 188 (107 mg). The Compound(210) was used in Example 96.

[1143]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48-1.73 (6H, m), 1.92-2.00 (4H,m), 3.18-3.24 (4H, m), 3.48-3.57 (1H, m), 3.88-4.01 (1H, m), 4.10 (2H,s), 4.87-4.93 (1H, m), 6.42-6.52 (3H, m), 7.25-7.37 (3H, m), 7.46 (1H,d, J=16 Hz), 7.52 (2H, d, J=8 Hz);

[1144] MASS (ES+): m/z 447 (M+1).

[1145] Preparation 211

[1146] To a mixture of methyl (2E)-3-[4-(hydroxymethyl)phenyl]acrylate(1.0 g) and triethylamine (1.26 g) in dichloromethane (10 mL) wasdropwise added methanesulfonyl chloride (715 mg) in dichloromethane (5mL) in an ice bath. The resulting mixture was stirred at the sametemperature for 1 hr and then allowed to warm to ambient temperature.After stirring at ambient temperature for 3 hrs, the mixture wasconcentrated in vacuo. The residue was extracted with ethyl acetate (100mL), and washed with 10% aqueous citric acid (25 mL), saturated aqueoussodium bicarbonate (25 mL) and brine (25 mL). The organic phase wasseparated, dried over anhydrous sodium sulfate and evaporated in vacuoto give Compound (211) (655 mg) as a colorless amorphous solid, whichwas used in the next step without further purification.

[1147]¹H-NMR (300 MHz, CDCl₃, δ): 3.82 (3H, s), 4.59 (2H, s), 6.45 (1H,d, J=15.8 Hz), 7.41 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.4 Hz), 7.69 (1H,d, J=15.8 Hz).

[1148] Preparation 212

[1149] To a stirred solution of 4-phenyl-1H-imidazole (115 mg) inN,N-dimethylformamide (0.5 mL) was added sodium hydride (60% oildispersion, 31 mg) in an ice bath. The mixture was stirred at the sametemperature for 15 min and then allowed to warm to ambient temperature.After stirring at ambient temperature for 15 min, the mixture was cooledin an ice bath. To this mixture was dropwise added Compound (211) (180mg) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred atthe same temperature for 2 hrs. The mixture was extracted with ethylacetate (50 mL), and washed with saturated aqueous sodium bicarbonate(25 mL) and brine (25 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by preparative thin-layer chromatography eluting with a mixtureof ethyl acetate and hexane (3:1 v/v) to afford Compound (212) (135 mg)as a colorless oil.

[1150]¹H-NMR (300 MHz, CDCl₃, δ): 3.81 (3H, s), 5.17 (2H, s), 6.44 (1H,d, J=15.8 Hz), 7.17-7.29 (4H, m), 7.33-7.41 (2H, m), 7.53 (2H, d, J=8.4Hz), 7.63 (1H, d, J=15.8 Hz), 7.68 (1H, s), 7.76 (2H, d, J=8.4 Hz);

[1151] MASS (ES+): m/z 319 (M+1).

[1152] Preparation 213

[1153] Compound (213) was obtained from Compound (211) according to amanner similar to Preparation 212 (457 mg).

[1154]¹H-NMR (300 MHz, CDCl₃, δ): 2.40 (3H, s), 3.81 (3H, s), 5.10 (2H,s), 6.43 (1H, d, J=16.1 Hz), 7.13 (2H, d, J=6.7 Hz), 7.14 (1H, s), 7.22(1H, t, J=7.0 Hz), 7.36 (2H, t, J=8.1 Hz), 7.51 (2H, d, J=8.1 Hz), 7.67(1H, d, J=16.1 Hz), 7.74 (2H, d, J=7.0 Hz);

[1155] MASS (ES+): m/e 333 (M+1).

[1156] Preparation 214

[1157] Compound (214) was obtained from Compound (211) according to amanner similar to Preparation 212 (723 mg).

[1158]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.25 (3H, s), 3.72 (3H, s), 5.28(2H, s), 6.64 (1H, d, J=16.1 Hz), 7.20 (2H, d, J=8.4 Hz), 7.42 (2H, d,J=8.4 Hz), 7.64 (2H, d, J=8.4 Hz), 7.65 (1H, d, J=16.1 Hz), 7.74 (2H, d,J=8.1 Hz), 7.84 (1H, s);

[1159] MASS (ES+): m/z 367 (M+1)

[1160] Preparation 215

[1161] Compound (215) was obtained from tert-butyl(2E)-3-[3-chloromethylphenyl]acrylate according to a manner similar toPreparation 212 (308 mg).

[1162]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 5.16 (2H, s), 6.36 (1H,d, J=15.8 Hz), 7.18 (1H, d, J=1.1 Hz), 7.20 (1H, m), 7.23 (1H, t, J=7.4Hz), 7.34-7.41 (4H, m), 7.48 (1H, d, J=7.7 Hz), 7.54 (1H, d, J=16.1 Hz),7.61 (1H, d, J=1.1 Hz), 7.76 (2H, dd, J=8.4, 1.5 Hz);

[1163] MASS (ES+): m/z 361 (M+1).

[1164] Preparation 216

[1165] Compound (216) was obtained from tert-butyl(2E)-3-[3-chloromethylphenyl]acrylate according to a manner similar toPreparation 212 (418 mg).

[1166]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 2.27 (3H, s), 5.12 (2H,s), 6.34 (1H, d, J=16.1 Hz), 7.08-(1H, br.d, J=7.7 Hz), 7.24 (1H, s),7.37 (2H, d, J=8.38 Hz), 7.38 (1H, t, J=7.8 Hz), 7.47 (1H, d, J=8.1 Hz),7.54 (1H, d, J=15.8 Hz), 7.60 (2H, d, J=8.8 Hz);

[1167] MASS (ES+): m/z 409 (M+1).

[1168] Preparation 217

[1169] Compound (217) was obtained from Compound (211) according to amanner similar to Preparation 212 (354 mg).

[1170]¹H-NMR (300 MHz, CDCl₃, δ): 3.81 (3H, s), 5.24 (2H, s), 6.43 (1H,d, J=16.1 Hz), 6.98 (1H, s), 7.06-7.14 (3H, m), 7.20-7.23 (1H, m),7.36-7.46 (3H, m), 7.47-7.57 (3H, m), 7.67 (1H, d, J=16.1 Hz);

[1171] MASS (ES+): m/z 319 (M+1).

[1172] Preparation 218

[1173] Compound (218) was obtained as a mixture of two regioisomers fromCompound (211) according to a manner similar to Preparation 212 (291mg).

[1174]¹H-NMR (300 MHz, CDCl₃, δ): (for a mixture of two regioisomers)2.09 (1.2H, s), 2.22 (1.8H, s), 3.81 (3H, s), 5.06 (1.2H, s), 5.08(0.8H, s), 6.43 (1H, d, J=16.1 Hz), 6.60 (0.6H, s), 6.85 (0.4H, s), 7.05(0.8H, d, J=8.1 Hz), 7.16 (1.2H, d, J=8.1 Hz), 7.44-7.55 (3H, m), 7.66(1H, d, J=16.1 Hz);

[1175] MASS (ES+): (for a mixture of two regioisomers) m/z 257 (M+1).

[1176] Preparation 219

[1177] To a stirred solution of Compound (212) (185 mg) in a mixture ofmethanol (1 mL) and 1,4-dioxane (1 mL) was added 1N sodium hydroxide(0.87 mL) at ambient temperature. The resulting solution was stirred atthe same temperature for 2 hrs. The mixture was cooled in an ice bathand to this mixture was added concentrated hydrochloric acid to acidifythe mixture. The precipitate was filtered and washed with 50% aqueousmethanol (1 mL) to afford Compound (219) (130 mg) as a white amorphoussolid.

[1178]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.47 (2H, s), 6.58 (1H, d, J=16.1Hz), 7.38-7.55 (5H, m), 7.60 (1H, d, J=16.1 Hz), 7.77 (2H, d, J=8.4 Hz),7.84 (2H, d, J=7.0 Hz), 8.25 (1H, s), 9.35 (1H, s);

[1179] MASS (ES+): m/z 305 (M+1).

[1180] Preparation 220

[1181] Compound (220) was obtained from Compound (213) according to amanner similar to Preparation 219 (357 mg).

[1182]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.68 (3H, s), 5.42 (2H, s), 6.58(1H, d, J=16.1 Hz), 7.42 (1H, t, J=7.7 Hz), 7.43 (2H, d, J=8.4 Hz), 7.51(2H, t, J=7.5 Hz), 7.60 (1H, d, J=16.1 Hz), 7.75 (2H, d, J=8.4 Hz), 7.83(2H, d, J=7.3 Hz), 8.14 (1H, s);

[1183] MASS (EI+) 319 (M+1).

[1184] Preparation 221

[1185] Compound (221) was obtained from Compound (214) according to amanner similar to Preparation 219 (564 mg).

[1186]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.25 (3H, s), 5.30 (2H, s), 6.52(1H, d, J=16.1 Hz), 7.21 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.4 Hz), 7.57(1H, d, J=15.8 Hz), 7.64 (2H, d, J=8.1 Hz), 7.70 (2H, d, J=8.1 Hz), 7.94(1H, s);

[1187] MASS (ES+): m/z 353 (M+1)

[1188] Preparation 222

[1189] To a stirred solution of Compound (219) (105 mg) inN,N-dimethylformamide (1.5 mL) were successively added1-hydroxybenztriazole (61 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine(49 mg) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (86 mg) in an ice bath, and the resulting mixture wasstirred at ambient temperature for three days. The mixture was extractedwith ethyl acetate (50 mL), and washed with saturated aqueous sodiumbicarbonate (25 mL) and brine (25 mL). The organic layer was dried overanhydrous sodium sulfate, and concentrated in vacuo. The residue waspurified by preparative thin-layer chromatography eluting with a mixtureof methanol and chloroform (10:90 v/v) to afford Compound (222) (120 mg)as a colorless viscous oil. The Compound (222) was used in Example 67.

[1190]¹H-NMR (300 MHz, CDCl₃, δ): 1.50-1.97 (6H, m), 3.60-3.72 (1H, m),3.90-4.05 (1H, m), 5.02 (1H, br.s), 5.17 (2H, s), 7.14-7.30 (6H, m),7.32-7.42 (2H, m), 7.44-7.56 (2H, m), 7.62-7.82 (3H, m);

[1191] MASS (ES+): m/z 404 (M+1)

[1192] Preparation 223

[1193] Compound (223) was obtained from Compound (220) according to amanner similar to Preparation 203 (431 mg). The Compound (223) was usedin Example 78.

[1194]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 2.29(3H, s), 3.52 (1H, m), 3.94 (1H, m), 4.90 (1H, s), 5.21 (2H, s), 6.49(1H, d, J=16.8 Hz), 7.16 (1H, t, J=7.5 Hz), 7.24 (2H, d, J=8.1 Hz), 7.32(2H, t, J=7.9 Hz), 7.47 (1H, d, J=16.8 Hz), 7.58 (2H, d, J=8.1 Hz), 7.63(1H, s), 7.71 (2H, d, J=7.0 Hz);

[1195] MASS (ES+): m/e 418 (M+1).

[1196] Preparation 224

[1197] Compound (224) was obtained from Compound (221) according to amanner similar to Preparation 203 (569 mg). The Compound (224) was usedin Example 79.

[1198]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 2.25(3H, s), 3.53 (1H, m), 3.95 (1H, m), 4.90 (1H, s), 5.27 (2H, s), 6.48(1H, d, J=15.8 Hz), 7.21 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.4 Hz), 7.47(1H, d, J=15.8 Hz), 7.58 (2H, d, J=8.1 Hz), 7.65 (2H, d, J=8.4 Hz), 7.84(1H, s);

[1199] MASS (ES+): m/z 452 (M+1).

[1200] Preparation 225

[1201] Compound (225) was obtained from(2E)-3-[4-(1H-imidazol-1-ylmethyl)phenyl]acrylic acid according to amanner similar to Preparation 203 (388 mg). The Compound (225) was usedin Example 95.

[1202]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.42-1.78 (6H, m), 3.53 (1H, m),3.95 (1H, m), 4.90 (1H, m), 5.23 (2H, s), 6.49 (1H, d, J=16 Hz), 6.93(1H, s), 7.21 (1H, s), 7.27 (2×1H, d, J=8 Hz), 7.47 (1H, d, J=16 Hz),7.56 (2×1H, d, J=8 Hz), 7.80 (1H, s), 11.25 (1H, s);

[1203] MASS (ES+): m/e 328.

[1204] Preparation 226

[1205] To a stirred solution of Compound (250) (125 mg, described laterin Preparation 250) in acetonitrile (2 mL) was added N-chlorosuccinimide(70 mg) in an ice bath. The mixture was stirred at ambient temperaturefor 2 days. The mixture was concentrated in vacuo and the residue waspurified by preparative thin-layer chromatography eluting with a mixtureof methanol and chloroform (4:96 v/v) to afford Compound (226) (100 mg)as a yellow oil.

[1206]¹H-NMR (300 MHz, CDCl₃, δ): 1.52 (9H, s), 4.09 (2H, s), 6.33 (1H,d, J=16.1 Hz), 7.21-7.44 (7H, m), 7.51 (1H, d, J=16.1 Hz), 7.59 (2H, d,J=7.3 Hz);

[1207] MASS (ES+): m/z 395 (M+1).

[1208] Preparation 227

[1209] Compound (227) was obtained from Compound (245) described lateraccording to a manner similar to Preparation 226 (230 mg).

[1210]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 4.09 (2H, s), 6.32 (1H,d, J=15.8 Hz), 7.27 (2H, d, J=7.7 Hz), 7.29 (1H, t, J=7.7 Hz), 7.40 (2H,t, J=7.4 Hz), 7.45 (2H, d, J=8.1 Hz), 7.53 (1H, d, J=16.1 Hz), 7.57 (2H,d, J=8.1 Hz);

[1211] MASS (ES+): m/e 395 (M+1).

[1212] Preparation 228

[1213] Compound (228) was obtained from Compound (251) described lateraccording to a manner similar to Preparation 226 (157 mg).

[1214]¹H-NMR (300 MHz, CDCl₃, δ): 3.80 (3H, s), 3.97 (2H, s), 6.25 (1H,d, J=16.1 Hz), 6.90 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.1 Hz), 7.32 (2H,d, J=8.1 Hz), 7.44 (1H, d, J=16.1 Hz), 7.54 (2H, d, J=8.8 Hz);

[1215] MASS (ES+): m/e 425 (M+1)

[1216] Preparation 229

[1217] To a solution of Compound (6) (4.1 g) in DMF (41 mL) were addedHOBt (2.75 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI,3.15 g) at 5° C. To the mixture was slowly added2-amino-1-phenylethanone hydrochloride (2.82 g) at 5° C. The mixture wasallowed to warm to ambient temperature and stirred for 2 hrs at the sametemperature. The resulting mixture was poured into water (100 mL) andextracted with AcOEt. The organic phase was sequentially washed withNH₄Cl, NaHCO₃ and brine, and dried over NaSO₄. The solvent was removedin vacuo, and the residue was purified by silica gel flash columnchromatography eluting with CHCl₃: MeOH=95:5 to give pale yellow solid.The resulting solid was triturated with isopropyl ether to give Compound(229) (5.425 g) as pale yellow powder.

[1218]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (9H, s), 3.69 (2H, s), 4.75(2H, d, J=4.0 Hz), 6.38 (1H, d, J=16.1 Hz), 7.35 (2H, d, J=8.1 Hz),7.47-7.56 (1+1+2+2H, m), 7.61 (1H, m), 7.95 (2H, d, J=8.4 Hz);

[1219] MASS (ES+): m/e 380 (M+1).

[1220] Preparation 230

[1221] Compound (230) was obtained from Compound (26) according to amanner similar to Preparation 229 (1.73 g).

[1222]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 3.67 (2H, s), 3.70 (3H,s), 6.19 (1H, d, J=7.3 Hz), 6.38 (1H, d, J=16.1 Hz), 6.85 (1H, br.d,J=7.3 Hz), 7.25-7.59 (7H, m), 7.60-7.68 (1H, m), 8.06-8.13 (2H, m);

[1223] MASS (ES−): m/z 436(M−1).

[1224] Preparation 231

[1225] Compound (231) was obtained from Compound (6) according to amanner similar to Preparation 229 (5.69 g).

[1226]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.67 (2H, s), 3.70 (3H,s), 6.12 (1H, d, J=7.0 Hz), 6.36 (1H, d, J=16.1 Hz), 6.82 (1H, br.d,J=7.0 Hz), 7.30 (2H, d, J=8.1 Hz), 7.44-7.53 (4H, m), 7.57 (1H, d,J=16.1 Hz), 8.03 (2H, d, J=8.8 Hz);

[1227] MASS (ES+): m/z 472 (M+1).

[1228] Preparation 232

[1229] Compound (232) was obtained from Compound (6) according to amanner similar to Preparation 229 (3.22 g).

[1230]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (3×3H, s), 3.57 (2H, s), 4.61(2H, d, J=5.5 Hz), 6.49 (1H, d, J=16 Hz), 7.30-7.42 (4H, m), 7.53 (1H,d, J=16 Hz), 7.63 (2×1H, d, J=8.5 Hz), 8.02-8.11 (2H, m), 8.48 (1H, t,J=5.5 Hz);

[1231] MASS (ES−): m/z 442 (M+HCO₂H−1).

[1232] Preparation 233

[1233] Compound (233) was obtained from Compound (6) according to amanner similar to Preparation 229 (1.74 g).

[1234]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.68 (2H, s), 4.71 (2H,d, J=5.5 Hz), 6.37 (2H, d, J=16.1 Hz), 6.50 (1H, br.s), 7.34 (2H, d,J=8.1 Hz), 7.47 (2H, d, J=8.4 Hz), 7.52 (2H, d, J=8.1 Hz), 7.58 (1H, d,J=16.1 Hz), 7.89 (2H, d, J=8.4 Hz);

[1235] MASS (ES+): m/z 414 (M+1).

[1236] Preparation 234

[1237] Compound (234) was obtained from Compound (26) according to amanner similar to Preparation 229 (1.95 g).

[1238]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 3.68 (2H, s), 4.75 (2H,d, J=4.4 Hz), 6.40 (1H, d, J=16.1 Hz), 6.56 (1H, br.s), 7.25-7.70 (8H,m), 7.91-8.02 (2H, m);

[1239] MASS (ES+): m/z 380 (M+1).

[1240] Preparation 235

[1241] Compound (235) was obtained from Compound (6) according to amanner similar to Preparation 229 (2.74 g).

[1242]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.68 (2H, s), 3.88 (3H,s), 4.68 (2H, d, J=4.4 Hz), 6.37 (1H, d, J=15.8 Hz), 6.95 (2H, d, J=9.1Hz), 7.34 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz), 7.58 (1H, d, J=16.1Hz), 7.92 (2H, d, J=8.8 Hz);

[1243] MASS (ES+): m/e 410 (M+1)

[1244] Preparation 236

[1245] Compound (236) was obtained from Compound (6) according to amanner similar to Preparation 229 (2.86 g).

[1246]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.69 (2H, s), 3.85 (3H,s), 4.73 (2H, d, J=4.4 Hz), 6.73 (2H, d, J=15.8 Hz), 7.16 (1H, dd,J=8.1, 2.6 Hz), 7.34 (2H, d, J=8.1 Hz), 7.39 (1H, t, J=8.1 Hz), 7.45(1H, m), 7.52 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=16.1 Hz);

[1247] MASS (ES+): m/e 410 (M+1).

[1248] Preparation 237

[1249] Compound (237) was obtained from Compound (6) according to amanner similar to Preparation 229 (1.82 g).

[1250]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.66 (2H, s), 3.93 (3H,s), 4.69 (2H, d, J=4.4 Hz), 6.37 (1H, d, J=16.1 Hz), 6.63 (1H, br), 7.00(1H, t, J=8.4 Hz), 7.03 (1H, t, J=7.7 Hz), 7.35 (2H, d, J=8.4 Hz), 7.51(2H, d, J=8.1 Hz), 7.58 (1H, d, J=16.1 Hz), 7.90 (1H, dd, J=7.7, 1.8Hz);

[1251] MASS (ES+): m/e 410 (M+1).

[1252] Preparation 238

[1253] Compound (238) was obtained from 4-iodophenylacetic acidaccording to a manner similar to Preparation 229 (4.20 g).

[1254]¹H-NMR (300 MHz, CDCl₃, δ): 3.61 (2H, s), 4.74 (2H, d, J=4.4 Hz),7.09 (2H, d, J=8.4 Hz), 7.49 (2H, t, J=7.4 Hz), 7.63 (1H, t, J=7.4 Hz),7.70 (2H, d, J=8.4 Hz), 7.95 (2H, d, J=7.4 Hz);

[1255] MASS (ES+): m/e 380 (M+1).

[1256] Preparation 239

[1257] Compound (239) was obtained from Compound (6) according to amanner similar to Preparation 229 (600 mg).

[1258]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (9H, s), 1.58-1.84 (12H, m),1.99-2.10 (3H, m), 3.61 (2H, s), 4.21 (2H, d, J=4.4 Hz), 6.35 (1H, d,J=16.1 Hz), 7.30 (2H, d, J=8.1 Hz), 7.50 (2H, d, J=8.1 Hz), 7.56 (1H, d,J=16.1 Hz);

[1259] MASS (ES+): m/z 438 (M+1).

[1260] Preparation 240

[1261] Compound (240) was obtained from Compound (6) according to amanner similar to Preparation 229 (231 mg).

[1262]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.68 (2H, s), 3.69 (3H,s), 6.18 (1H, d, J=7.3 Hz), 6.36 (1H, d, J=15.8 Hz), 7.30 (2H, d, J=8.1Hz), 7.51 (4H, m), 7.62 (2H, m), 8.08 (2H, d, J=7.0 Hz);

[1263] MASS (ES+): m/e 438 (M+1).

[1264] Preparation 241

[1265] Compound (241) was obtained according to a manner similar toPreparation 229 (1.33 g).

[1266]¹H-NMR (300 MHz, CDCl₃, δ): 1.17 (9H, s), 1.54 (9H, s), 3.62 (2H,s), 4.25 (2H, d, J=4.4 Hz), 6.36 (1H, d, J=15.8 Hz), 7.31 (2H, d, J=8.4Hz), 7.51 (2H, d, J=8.1 Hz), 7.57 (1H, d, J=16.1 Hz);

[1267] MASS (ES+): m/e 360 (M+1)

[1268] Preparation 242

[1269] Compound (242) was obtained from Compound (6) according to amanner similar to Preparation 229 (1.58 g).

[1270]¹H-NMR (300 MHz, CDCl₃, δ): 1.12 (3H, t, J=7.0 Hz), 1.53 (9H, s),3.67 (2H, s), 4.13 (2H, q, J=7.4 Hz), 6.15 (1H, d, J=7.3 Hz), 6.36 (1H,d, J=15.8 Hz), 6.86 (1H, br.d, J=6.6 Hz), 7.31 (2H, d, J=8.1 Hz), 7.48(2H, t, J=7.4 Hz), 7.50 (2H, d, J=8.1 Hz), 7.57 (1H, d, J=16.1 Hz), 7.63(1H, t, J=7.4 Hz), 8.08 (2H, d, J=8.1 Hz);

[1271] MASS (ES+): m/z 452 (M+1).

[1272] Preparation 243

[1273] Compound (243) was obtained from Compound (6) according to amanner similar to Preparation 229 (200 mg).

[1274]¹H-NMR (300 MHz, CDCl₃, δ): 1.30 (4H, m), 1.53 (9H, s), 1.64 (2H,m), 1.80 (4H, m), 2.36 (1H, m), 3.62 (2H, s), 4.17 (2H, d, J=4.4 Hz),6.35 (1H, d, J=16.1 Hz), 7.30 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.1 Hz),7.56 (1H, d, J=15.8 Hz);

[1275] MASS (ES+): m/z 386 (M+1).

[1276] Preparation 244

[1277] Compound (244) was obtained from Compound (6) according to amanner similar to Preparation 229 (866 mg).

[1278]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7 Hz), 3.60 (2H, s),3.71 (2H, s), 4.16 (2H, d, J=5 Hz), 4.27 (2H, q, J=7 Hz), 6.42 (1H, d,J=16 Hz), 7.16-7.37 (7H, m), 7.50 (2H, d, J=8 Hz), 7.66 (1H, d, J=16Hz);

[1279] MASS (ES+): m/z 366 (M+1)

[1280] Preparation 245

[1281] To a suspension of Compound (229) (5.42 g) in xylene (50 mL) wereadded AcONH₄ and AcOH, and the mixture was refluxed for 3 hrs withazeotropic removal of water. The resulting solution was cooled toambient temperature and poured into saturated aqueous NaHCO₃ solution(100 mL) and extracted with AcOEt. The organic layer was washed withsaturated aqueous NaHCO₃, water and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo, and the residual solid was triturated withisopropyl ether to give Compound (245) (4.56 g) as pale yellow powder.

[1282]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 4.19 (2H, s), 6.35 (1H,d, J=15.7 Hz), 7.21 (1H, s), 7.25 (1H, t, J=7.0 Hz), 7.29 (2H, d, J=8.4Hz), 7.38 (2H, t, J=7.0 Hz), 7.48 (2H, d, J=7.7 Hz), 7.56 (1H, d, J=15.4Hz), 7.69 (2H, br.d);

[1283] MASS (ES+): m/e 361 (M+1).

[1284] Preparation 246

[1285] Compound (246) was obtained from Compound (230) according to amanner similar to Preparation 245 (1.10 g).

[1286]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 3.82 (3H, s), 4.17 (2H,s), 6.36 (1H, d, J=16.1 Hz), 7.22-7.48 (9H, m), 7.54 (1H, d, J=16.1 Hz),7.74-7.87 (1H, m);

[1287] MASS (ES+): m/z 419 (M+1).

[1288] Preparation 247

[1289] Compound (247) was obtained from Compound (231) according to amanner similar to Preparation 245 (3.8 g).

[1290]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.82 (3H, s), 4.17 (2H,s), 6.36 (1H, d, J=16.1 Hz), 7.29 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=8.1Hz), 7.49 (2H, d, J=8.1 Hz), 7.55 (1H, d, J=16.1 Hz), 7.78-7.90 (2H, m);

[1291] MASS (ES+): m/z 453 (M+1).

[1292] Preparation 248

[1293] Compound (248) was obtained from Compound (232) according to amanner similar to Preparation 245 (2.08 g).

[1294]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (3×3H, s), 4.16 (2H, s), 6.36(1H, d, J=16.2 Hz), 7.06 (2×1H, dd, J=8.8, 8.7 Hz), 7.14 (1H, s), 7.27(2×1H, d, J=8 Hz), 7.46 (2×1H, d, J=8 Hz), 7.54 (1H, d, J=16.2 Hz), 7.73(2H, m), 8.84 (1H, br);

[1295] MASS (ES+): m/z 379.

[1296] Preparation 249

[1297] Compound (249) was obtained from Compound (233) according to amanner similar to Preparation 245 (1.12 g).

[1298]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 4.17 (2H, s), 6.33 (1H,d, J=16.1 Hz), 7.17 (1H, s), 7.27 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=8.4Hz), 7.46 (2H, d, J=8.1 Hz), 7.53 (2H, d, J=16.1 Hz), 7.64 (2H, d, J=8.4Hz);

[1299] MASS (ES+): m/z 395 (M+1)

[1300] Preparation 250

[1301] Compound (250) was obtained from Compound (234) according to amanner similar to Preparation 245 (1.28 g).

[1302]¹H-NMR (300 MHz, CDCl₃, δ): 1.52 (9H, s), 4.16 (2H, s), 6.33 (1H,d, J=16.1 Hz), 7.17-7.44 (8H, m), 7.52 (1H, d, J=16.1 Hz), 7.64-7.73(2H, m);

[1303] MASS (ES+): m/z 361 (M+1).

[1304] Preparation 251

[1305] Compound (251) was obtained from Compound (235) according to amanner similar to Preparation 245 (2.00 g).

[1306]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.82 (3H, s), 4.16 (2H,s), 6.34 (1H, d, J=15.8 Hz), 6.91 (2H, d, J=8.8 Hz), 7.10 (1H, s), 7.27(2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.55 (1H, d, J=16.1 Hz), 7.60(2H, br.d);

[1307] MASS (ES+): m/z 391 (M+1)

[1308] Preparation 252

[1309] Compound (252) was obtained from Compound (236) according to amanner similar to Preparation 245 (2.72 g).

[1310]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 3.78 (3H, s), 4.05 (2H,s), 6.28 (1H, d, J=16.1 Hz), 6.78 (1H, m), 7.17 (2H, d, J=8.1 Hz), 7.18(1H, s), 7.247 (2H, d, J=5.17 Hz), 7.37 (2H, d, J=8.4 Hz), 7.49 (1H, d,J=15.7 Hz);

[1311] MASS (ES+): m/e 391 (M+1).

[1312] Preparation 253

[1313] Compound (253) was obtained from Compound (237) according to amanner similar to Preparation 245 (1.56 g).

[1314]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.85 (3H, s), 4.19 (2H,s, J=16.1 Hz), 6.34 (1H, d, J=8.4 Hz), 6.76 (1H, d, J=7.5 Hz), 7.00 (1H,t, J=7.5 Hz), 7.22 (1H, t, J=8.1 Hz), 7.30 (2H, d), 7.41 (1H, s, J=8.4Hz), 7.48 (2H, d, J=16.1 Hz), 7.72 (1H, d, J=8.4 Hz), 7.76 (1H, br.d);

[1315] MASS (ES+): m/e 391 (M+1).

[1316] Preparation 254

[1317] Compound (254) was obtained from Compound (238) according to amanner similar to Preparation 245 (4.00 g).

[1318]¹H-NMR (300 MHz, CDCl₃, δ): 4.08 (2H, s), 7.03 (2H, d, J=8.4 Hz),7.24 (1H, t, J=7.4 Hz), 7.37 (2H, t, J=7.7 Hz), 7.65 (2+2H, d, J=8.4Hz);

[1319] MASS (ES+): m/e 361 (M+1).

[1320] Preparation 255

[1321] Compound (255) was obtained from N-(2-oxo-2-phenylethyl)acetamideaccording to a manner similar to Preparation 245 (803 mg).

[1322]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.48 (3H, s), 7.20 (1H, s), 7.23(1H, t, J=8.1 Hz), 7.37 (2H, t, J=7.7 Hz), 7.69 (2H, d, J=8.1 Hz).

[1323] Preparation 256

[1324] Compound (256) was obtained from Compound (239) according to amanner similar to Preparation 245 (460 mg).

[1325]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 1.69-1.81 (6H, m),1.83-1.91 (6H, m), 1.99-2.08 (3H, m), 4.09 (2H, s), 6.34 (1H, d, J=16.1Hz), 6.57 (1H, s), 7.23 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.2 Hz), 7.55(1H, d, J=16.1 Hz);

[1326] MASS (ES+): m/z 419 (M+1).

[1327] Preparation 257

[1328] Compound (257) was obtained from Compound (240) according to amanner similar to Preparation 245 (58 mg).

[1329]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.82 (3H, s), 4.17 (2H,s), 6.35 (1H, d, J=16.1 Hz), 7.28 (2H, d, J=7.7 Hz), 7.39 (3H, m), 7.48(2H, d, J=7.7 Hz), 7.55 (1H, d, J=16.1 Hz), 7.87 (2H, br.);

[1330] MASS (ES+): m/e 419 (M+1).

[1331] Preparation 258

[1332] Compound (258) was obtained from Compound (241) according to amanner similar to Preparation 245 (1.06 g).

[1333]¹H-NMR (300 MHz, CDCl₃, δ): 1.28 (9H, s), 1.53 (9H, s), 4.07 (2H,s), 6.31 (1H, d, J=16.1 Hz), 6.60 (1H, s), 7.21 (2H, d, J=8.1 Hz), 7.43(2H, d, J=8.4 Hz), 7.52 (1H, d, J=15.8 Hz);

[1334] MASS (ES+): m/e 341 (M+1).

[1335] Preparation 259

[1336] Compound (259) was obtained from Compound (243) according to amanner similar to Preparation 245 (80 mg).

[1337]¹H-NMR (300 MHz, CDCl₃, δ): 1.32 (4H, m), 1.53 (9H, s), 1.73 (4H,m), 1.98 (2H, m), 2.50 (1H, m), 4.04 (2H, s), 6.31 (1H, d, J=16.1 Hz),6.58 (1H, s), 7.20 (2H, d, J=8.1 Hz), 7.42 (2H, d, J=8.1 Hz), 7.52 (1H,d, J=16.1 Hz);

[1338] MASS (ES+): m/z 367 (M+1).

[1339] Preparation 260

[1340] Compound (260) was obtained from Compound (244) according to amanner similar to Preparation 245 (232 mg).

[1341]¹H-NMR (300 MHz, CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 3.92 (2H, s),4.09 (2H, s), 4.26 (2H, q, J=7 Hz), 6.41 (1H, d, J=16 Hz), 7.21-7.33(7H, m), 7.48 (2H, d, J=8 Hz), 7.65 (1H, d, J=16 Hz);

[1342] MASS (ES+): m/z 347 (M+1).

[1343] Preparation 261

[1344] To a solution of Compound (297) (2.56 g, described later inPreparation 297 in dichloromethane) (17 mL) was added trifluoroaceticacid (2.74 mL), and the mixture was stirred for 1 hr. The solvent wasremoved in vacuo, and the residue was triturated with isopropyl ether togive Compound (261) (2.83 g) as colorless powder.

[1345]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.37 (2H, s), 6.54 (1H, d, J=15.8Hz), 7.39 (2H, d, J=8.1 Hz), 7.43 (1H, t, J=7.7 Hz), 7.53 (2H, t, J=8.1Hz), 7.58 (1H, d, J=15.8 Hz), 7.72 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.1Hz), 8.05 (1H, s);

[1346] MASS (ES+): m/e 305 (M+1).

[1347] Preparation 262

[1348] Compound (262) was obtained from Compound (246) according to amanner similar to Preparation 261 (1.55 g).

[1349]¹H-NMR (300 MHz, CDCl₃—CD₃OD (10:1), 6): 3.87 (3H, s), 4.35 (2H,s), 6.46 (1H, d, J=16.2 Hz), 7.10-7.76 (10H, m);

[1350] MASS (ES+): m/z 369 (M+1, free).

[1351] Preparation 263

[1352] Compound (263) was obtained from Compound (251) according to amanner similar to Preparation 261 (2.32 g).

[1353]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.81 (3H, s), 4.37 (2H, s), 6.55(1H, d, J=16.1 Hz), 7.10 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.4 Hz), 7.59(1H, d, J=16.1 Hz), 7.71 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.4 Hz), 7.95(1H, s);

[1354] MASS (ES+): m/z 335 (M+1).

[1355] Preparation 264

[1356] Compound (264) was obtained from Compound (252) according to amanner similar to Preparation 261 (1.27 g).

[1357]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.83 (3H, s), 4.39 (2H, s), 6.55(1H, d, J=15.8 Hz), 7.02 (1H, d, J=8.1 Hz), 7.33-7.47 (5H, m), 7.60 (1H,d, J=15.8 Hz), 7.73 (2H, d, J=8.1 Hz), 8.11 (1H, s);

[1358] MASS: Not Detected.

[1359] Preparation 265

[1360] Compound (265) was obtained from Compound (253) according to amanner similar to Preparation 261 (1.24 g).

[1361]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.93 (3H, s), 4.40 (2H, s), 6.54(1H, d, J=16.1 Hz), 7.12 (1H, t, J=7.3 Hz), 7.22 (1H, d, J=7.7 Hz), 7.39(2H, d, J=8.1 Hz), 7.46 (1H, t, J=7.9 Hz), 7.58 (1H, d, J=16.1 Hz), 7.72(2H, d, J=8.1 Hz), 7.89 (1H, s);

[1362] MASS (ES+): m/e 335 (M+1)

[1363] Preparation 266

[1364] Compound (266) was obtained from Compound (293) described lateraccording to a manner similar to Preparation 261 (208 mg).

[1365]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.08 (2H, s), 6.05 (1H, d, J=16.1Hz), 7.35 (2H, d, J=8.4 Hz), 7.37 (1H, t, J=7.4 Hz), 7.49 (2H, d, J=7.4Hz), 7.57 (1H, d, J=16.1 Hz), 7.66 (2H, d, J=8.1 Hz), 7.71 (1H, d, J=7.0Hz);

[1366] MASS (ES+): m/e 383 (M+1).

[1367] Preparation 267

[1368] Compound (267) was obtained from Compound (227) according to amanner similar to Preparation 261 (234 mg).

[1369]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.03 (2H, s), 6.49 (1H, d, J=15.8Hz), 7.32 (1H, t, J=7.3 Hz), 7.34 (2H, d, J=8.4 Hz), 7.47 (2H, t, J=7.3Hz), 7.57 (1H, d, J=16.1 Hz), 7.65 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=7.3Hz);

[1370] MASS (ES+): m/e 339 (M+1).

[1371] Preparation 268

[1372] Compound (268) was obtained from Compound (294) described lateraccording to a manner similar to Preparation 261 (1.32 g).

[1373]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.72 (6H, s), 4.21 (2H, s), 4.39(2H, s), 6.52 (1H, d, J=15.8 Hz), 7.38 (2H, d, J=8.1 Hz), 7.47 (1H, m),7.54 (4H, m), 7.58 (1H, d, J=15.4 Hz), 7.68 (2H, d, J=8.4 Hz);

[1374] MASS (ES+): m/e 362 (M+1).

[1375] Preparation 269

[1376] Compound (269) was obtained from Compound (295) described lateraccording to a manner similar to Preparation 261 (412 mg).

[1377]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48 (2H, br.), 1.69 (4H, br.), 2.91(2H, br.), 3.27 (2H, br.), 4.24 (2H, s), 4.38 (2H, s), 6.53 (1H, d,J=16.1 Hz), 7.38 (2H, d, J=8.1 Hz), 7.47-7.61 (6H, m), 7.69 (2H, d,J=8.1 Hz);

[1378] MASS (ES+): m/e 402 (M+1).

[1379] Preparation 270

[1380] Compound (270) was obtained from Compound (296) described lateraccording to a manner similar to Preparation 261 (407 mg).

[1381]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.07 (4H, br.), 3.75 (4H, br.), 4.22(2H, s), 4.29 (2H, s), 6.52 (1H, d, J=15.7 Hz), 7.39 (2H, d, J=8.1 Hz),7.46 (1H, t, J=7.0 Hz), 7.53 (2H, t, J=7.0 Hz), 7.58 (1H, d, J=16.1 Hz),7.59 (2H, d, J=7.3 Hz), 7.68 (2H, d, J=8.1 Hz);

[1382] MASS (ES+): m/e 404 (M+1).

[1383] Preparation 271

[1384] Compound (271) was obtained from Compound (228) according to amanner similar to Preparation 261 (171 mg).

[1385]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.79 (3H, s), 4.03 (2H, s), 6.50(1H, d, J=16.1 Hz), 7.05 (2H, d, J=8.8 Hz), 7.34 (2H, d, J=8.1 Hz), 7.57(1H, d, J=15.8 Hz), 7.62 (2H, d, J=8.8 Hz), 7.65 (2H, d, J=8.1 Hz);

[1386] MASS (ES+): m/e 369 (M+1).

[1387] Preparation 272

[1388] Compound (272) was obtained from Compound (215) according to amanner similar to Preparation 261 (339 mg).

[1389]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.46 (2H, s), 6.60 (1H, d, J=16.1Hz), 7.43 (1H, t, J=7.0 Hz), 7.46-7.54 (4H, m), 7.61 (1H, d, J=16.1 Hz),7.72 (1H, m), 7.78 (2H, d, J=7.0 Hz), 7.84 (1H, s), 8.25 (1H, s), 9.29(1H, s);

[1390] MASS (ES+): m/e 305 (M+1).

[1391] Preparation 273

[1392] Compound (273) was obtained from Compound (218) according to amanner similar to Preparation 261 (491 mg).

[1393]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.30 (3H, s), 5.48 (2H, s), 6.57(1H, d, J=16.1 Hz), 7.34-7.52 (3H, m), 7.58 (1H, d, J=15.8 Hz), 7.60(4H, s), 7.71 (1H, s), 9.26 (1H, s);

[1394] MASS (ES+): m/e 353 (M+1).

[1395] Preparation 274

[1396] Compound (274) was obtained from Compound (257) according to amanner similar to Preparation 261 (65 mg).

[1397]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.78 (3H, s), 4.20 (2H, s), 6.51(1H, d, J=15.8 Hz), 7.38 (2H, d, J=7.7 Hz), 7.47 (3H, m), 7.57 (1H, d,J=15.8 Hz), 7.67 (2H, d, J=8.4 Hz), 7.76 (2H, m);

[1398] MASS (ES+): m/e 363 (M+1).

[1399] Preparation 275

[1400] Compound (275) was obtained from Compound (258) according to amanner similar to Preparation 261 (454 mg).

[1401]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.21 (9H, s), 4.32 (2H, s), 6.55(1H, d, J=16.1 Hz), 7.34 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=16.1 Hz),7.71 (2H, d, J=8.1 Hz);

[1402] MASS (ES+): m/e 285 (M+1).

[1403] Preparation 276

[1404] Compound (276) was obtained from Compound (259) according to amanner similar to Preparation 261 (98.5 mg).

[1405]¹H-NMR (300 MHz, DMSO-d, 6): 1.32 (4H, m), 1.72 (4H, m), 1.94 (2H,m), 2.47 (1H, m), 4.28 (2H, s), 6.54 (1H, d, J=15.8 Hz), 7.31 (1H, s),7.33 (2H, d, J=8.1 Hz), 7.58 (1H, d, J=15.4 Hz), 7.71 (2H, d, J=8.1 Hz);

[1406] MASS (ES+): m/z 311 (M+1) 0.116

[1407] Preparation 277

[1408] To a solution of Compound (261) (2.46 g) in DMF (30 mL) wereadded O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.66 g), HOBt (2.74 g)and EDCI (3.15 g) at ambient temperature, and the mixture was stirredfor 3 hrs. The resulting mixture was diluted with saturated aqueousNaHCO₃ solution and the precipitate was collected by filtration. Theobtained powder was washed with water and dried to give Compound (277)(2.46 g) as pale yellow powder. The obtained Compound (277) was used inExample 58.

[1409]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.70 (3H, br.), 3.51(1H, m), 3.96 (1H, m), 4.04 (2H, s), 4.90 (1H, s), 6.46 (1H, d, J=16.1Hz), 7.16 (1H, m), 7.31 (4H, m), 7.46 (1H, d, J=15.7 Hz), 7.51 (3H, m),7.73 (2H, d, J=7.3 Hz);

[1410] MASS (ES+): m/e 304 (M+1)

[1411] Preparation 278

[1412] Compound (278) was obtained from Compound (262) according to amanner similar to Preparation 277 (896 mg). The obtained Compound (278)was used in Example 59.

[1413]¹H-NMR (300 MHz, CDCl₃, δ): 1.48-1.86 (6H, m), 3.58-3.69 (1H, m)3.81 (3H, s), 3.91-4.09 (3H, m), 4.95 (1H, br.s), 6.09-6.30 (1H, m),7.17-7.31 (6H, m), 7.33-7.43 (4H, m), 7.74-7.84 (2H, m);

[1414] MASS (ES+): m/z 462 (M+1).

[1415] Preparation 279

[1416] Compound (279) was obtained from Compound (263) according to amanner similar to Preparation 277 (1.67 g). The obtained Compound (278)was used in Example 70.

[1417]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.53(1H, m), 3.76 (3H, s), 3.94 (1H, m), 4.08 (2H, s), 4.91 (1H, s), 6.47(1H, d, J=15.8 Hz), 6.94 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=8.1 Hz), 7.43(1H, s), 7.46 (1H, d, J=15.8 Hz), 7.54 (2H, d, J=7.7 Hz), 7.64 (2H, d,J=8.8 Hz);

[1418] MASS (ES+): m/z 434 (M+1).

[1419] Preparation 280

[1420] Compound (280) was obtained from Compound (264) according to amanner similar to Preparation 277 (758 mg). The obtained Compound (280)was used in Example 71.

[1421]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.52(1H, m), 3.78 (3H, s), 3.95 (1H, m), 4.04 (2H, s), 4.90 (1H, s), 6.46(1H, d, J=16.1 Hz), 6.74 (1H, d, J=8.1 Hz), 7.20-7.33 (5H, m), 7.46 (1H,d, J=15.8 Hz), 7.51 (1H, s), 7.52 (2H, d, J=8.1 Hz);

[1422] MASS (ES+): m/e 434 (M+1).

[1423] Preparation 281

[1424] Compound (281) was obtained from Compound (265) according to amanner similar to Preparation 277 (729 mg). The obtained Compound (281)was used in Example 72.

[1425]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.s), 1.69 (3H, br.s),3.53 (1H, m), 3.88 (3H, s), 3.95 (1H, m), 4.05 (2H, s), 4.90 (1H, s),6.46 (1H, d, J=16.3 Hz), 6.96 (1H, t, J=7.3 Hz), 7.03 (1H, d, J=8.1 Hz),7.17 (1H, t, J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz), 7.42 (1H, br.s), 7.46(1H, d, J=16.1 Hz), 7.52 (2H, d, J=8.1 Hz);

[1426] MASS (ES+): m/z 434 (M+1).

[1427] Preparation 282

[1428] Compound (282) was obtained from Compound (266) according to amanner similar to Preparation 277 (148 mg). The obtained Compound (282)was used in Example 73.

[1429]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.55(1H, m), 3.95 (1H, m), 4.02 (2H, s), 4.91 (1H, s), 6.48 (1H, d, J=16.1Hz), 7.32 (1H, t, J=7.0 Hz), 7.34 (2H, d, J=8.1 Hz), 7.46 (2H, t, J=7.3Hz), 7.46 (1H, d, J=15.4 Hz), 7.54 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=7.3Hz);

[1430] MASS (ES+): m/e 482 (M+1)

[1431] Preparation 283

[1432] Compound (283) was obtained from Compound (267) according to amanner similar to Preparation 277 (166 mg). The obtained Compound (283)was used in Example 74.

[1433]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.53(1H, m), 3.69 (1H, m), 4.02 (2H, s), 4.90 (1H, s), 6.47 (1H, d, J=16.1Hz), 7.32 (1H, t, J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 7.47 (2H, t, J=15.8Hz), 7.47 (1H, d, J=8.1 Hz), 7.54 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.1Hz);

[1434] MASS (ES+): m/e 438 (M+1).

[1435] Preparation 284

[1436] Compound (284) was obtained from Compound (268) according to amanner similar to Preparation 277 (811 mg). The obtained Compound (284)was used in Examples 90 and 111.

[1437]¹H-NMR (300 MHz, CDCl₃, δ): 1.51-1.67 (6H, br), 2.28 (6H, s), 3.60(1H, m), 3.94 (1H, m), 4.12 (2H, s), 4.71 (1H, s), 7.39 (3H, m), 7.59(2H, d, J=6.6 Hz), 7.61 (1H, d, J=16.8 Hz);

[1438] MASS (ES+): m/e 461 (M+1).

[1439] Preparation 285

[1440] Compound (285) was obtained from Compound (269) according to amanner similar to Preparation 277 (105 mg). The obtained Compound (285)was used in Example 75.

[1441]¹H-NMR (300 MHz, CDCl₃, δ): 1.45 (3H, br.), 1.59 (3+4H, br.), 1.84(2H, br.), 2.48 (4H, br.), 3.64 (1H, m), 3.71 (2H, s), 3.97 (1H, m),4.12 (2H, s), 5.01 (1H, s), 6.32 (1H, d, J=16.1 Hz), 7.26 (1+2H, m),7.39 (2+2H, m), 7.49 (1H, d, J=16.5 Hz), 7.59 (2H, d, J=7.0 Hz);

[1442] MASS (ES+): m/e 501 (M+1).

[1443] Preparation 286

[1444] Compound (286) was obtained from Compound (270) according to amanner similar to Preparation 277 (129 mg). The obtained Compound (286)was used in Example 76.

[1445]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 2.40(4H, br.), 3.52 (1H, m), 3.57 (4H, br.), 3.95 (1H, m), 4.00 (2H, s),4.90 (1H, s), 6.46 (1H, d, J=15.8 Hz), 7.23 (1H, br.), 7.33 (2H, d,J=8.4 Hz), 7.36 (2H, br.), 7.46 (1H, d, J=15.8 Hz), 7.51 (2H, d, J=8.1Hz), 7.70 (2H, br.);

[1446] MASS (ES+): m/e 503 (M+1)

[1447] Preparation 287

[1448] Compound (287) was obtained from Compound (271) according to amanner similar to Preparation 277 (108 mg). The obtained Compound (287)was used in Example 77.

[1449]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 3.54(1H, m), 3.79 (3H, s), 3.94 (1H, m), 3.98 (2H, s), 4.90 (1H, s), 6.47(1H, d, J=16.1 Hz), 7.04 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=7.7 Hz), 7.47(1H, d, J=15.4 Hz), 7.53 (2H, d, J=7.7 Hz), 7.61 (2H, d, J=8.8 Hz);

[1450] MASS (ES+): m/e 468 (M+1).

[1451] Preparation 288

[1452] Compound (288) was obtained from Compound (272) according to amanner similar to Preparation 277 (215 mg). The obtained Compound (288)was used in Example 80.

[1453]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 3.53(1H, m), 3.94 (1H, m), 4.90 (1H, s), 5.25 (2H, s), 6.50 (1H, d, J=16.1Hz), 7.18 (1H, t, J=7.3 Hz), 7.32 (3H, m), 7.38 (1H, d, J=15.4 Hz), 7.44(1H, d, J=7.3 Hz), 7.52 (1H, s), 7.56 (1H, s), 7.73 (3H, m), 7.86 (1H,s);

[1454] MASS (ES+): m/e 404 (M+1).

[1455] Preparation 289

[1456] Compound (289) was obtained from Compound (273) according to amanner similar to Preparation 277 (419 mg). The obtained Compound (289)was used in Example 81.

[1457]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 3.52(1H, m), 3.95 (1H, m), 4.91 (1H, s), 5.26 (2H, s), 6.48 (1H, d, J=15.8Hz), 7.19 (1H, d, J=7.7 Hz), 7.43 (5H, m), 7.51 (1H, s), 7.65 (2H, d,J=8.8 Hz), 7.86 (1H, s);

[1458] MASS (ES+): m/e 452 (M+1).

[1459] Preparation 290

[1460] Compound (290) was obtained from Compound (274) according to amanner similar to Preparation 277 (43 mg). The obtained Compound (290)was used in Example 84.

[1461]¹H-NMR (300 MHz, CDCl₃, δ): 1.60 (3H, br.), 1.81 (3H, br.), 6.64(1H, m), 3.82 (3H, s), 3.97 (1H, s), 4.03 (2H, s), 5.00 (1H, br.), 6.28(1H, br.), 7.12 (2H, br.), 7.32 (2H, br.), 7.39 (3H, m), 7.54 (1H, br.),7.79 (2H, br.);

[1462] MASS (ES+): m/e 462 (M+1).

[1463] Preparation 291

[1464] Compound (291) was obtained from Compound (275) according to amanner similar to Preparation 277 (85 mg). The obtained Compound (291)was used in Example 85.

[1465]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.53(1H, m), 3.94 (2H, s), 3.97 (1H, m), 4.91 (1H, s), 6.45 (1H, d, J=15.3Hz), 6.56 (1H, s), 7.27 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=16.1 Hz), 7.50(2H, d, J=8.8 Hz);

[1466] MASS (ES+): m/e 384 (M+1).

[1467] Preparation 292

[1468] Compound (292) was obtained from Compound (276) according to amanner similar to Preparation 277 (42 mg). The obtained Compound (292)was used in Example 110.

[1469]¹H-NMR (300 MHz, CDCl₃, δ): 1.30 (6H, m), 1.62-2.00 (10H, m), 2.51(1H, m), 3.67 (1H, m), 4.02 (1H, m), 4.02 (2H, s), 5.01 (1H, s), 6.37(1H, br.), 6.58 (1H, s, J=8.0 Hz), 7.23 (2H, d, J=7.7 Hz), 7.43 (2H, d,J=16.1 Hz), 7.62 (1H, d);

[1470] MASS (ES+): m/z 410 (M+1)

[1471] Preparation 293

[1472] To a suspension of Compound (245) (2.0 g) in MeCN (20 mL) wasadded N-bromosuccinimide (988 mg) at 5° C. and the mixture was stirredfor 0.5 hr at 5° C. The mixture was poured into 5% aqueous NaHSO₃solution (100 mL), and the mixture was extracted with AcOEt. The organiclayer was washed with saturated aqueous NaHCO₃ solution and brine, anddried over Na₂SO₄. The solvent was removed in vacuo and the residualbrown oil was purified by Silica gel flash column chromatography elutingwith Hexane: AcOEt=1:1 to give Compound (293) (1.68 g) as orange form.

[1473]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 4.13 (2H, s), 6.34 (1H,d, J=16.1 Hz), 7.28 (2H, d, J=8.1 Hz), 7.31 (1H, t, J=7.4 Hz), 7.40 (2H,t, J=7.4 Hz), 7.47 (2H, d, J=8.1 Hz), 7.54 (1H, d, J=16.1 Hz), 7.57 (2H,d, J=7.4 Hz);

[1474] MASS (ES+): m/e 439 (M+1)

[1475] Preparation 294

[1476] To a solution of Compound (245) (1.0 g) were addedN,N-dimethylamine hydrochloride (339 mg) and paraformaldehyde (125 mg),and the mixture was heated at 90° C. for 1 hr. The reaction mixture waspoured into saturated aqueous NaHCO₃ solution and extracted with AcOEt.The organic phase was washed with saturated aqueous NaHCO₃ solution,water and brine, and dried over Na₂SO₄. The solvent was removed in vacuoto give Compound (294) (742 mg) as yellow form.

[1477]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 2.23 (6H, s), 3.58 (2H,s), 4.16 (2H, s), 6.35 (1H, d, J=15.8 Hz), 7.29 (1H, t, J=8.1 Hz), 7.30(2H, d, J=8.1 Hz), 7.39 (2H, t, J=8.1 Hz), 7.48 (2H, t, J=8.1 Hz), 7.57(1H, d, J=16.1 Hz), 7.58 (1H, br.);

[1478] MASS (ES+): m/e 418 (M+1).

[1479] Preparation 295

[1480] Compound (295) was obtained from Compound (245) according to amanner similar to Preparation 294 (243 mg).

[1481]¹H-NMR (300 MHz, CDCl₃, δ): 1.44 (2H, br.), 1.53 (9+4H, br.), 2.42(4H, br.), 3.63 (2H, s), 4.11 (2H, s), 6.34 (1H, d, J=15.8 Hz), 7.27(1H, t, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz), 7.37 (2H, t, J=8.1 Hz), 7.45(2H, d, J=8.4 Hz), 7.55 (1H, d, J=15.7 Hz), 7.58 (2H, d, J=8.1 Hz);

[1482] MASS (ES+): m/e 458 (M+1).

[1483] Preparation 296

[1484] Compound (296) was obtained from Compound (245) according to amanner similar to Preparation 294 (297 mg).

[1485]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 2.48 (4H, br.), 3.64(2H, s), 3.68 (4H, br.), 4.15 (2H, s), 6.35 (1H, d, J=16.1 Hz), 7.28(1H, t, J=8.1 Hz), 7.29 (2H, d, J=8.1 Hz), 7.39 (2H, t, J=7.5 Hz), 7.48(2H, d, J=8.4 Hz), 7.56 (2H, br.), 7.56 (1H, d, J=16.1 Hz);

[1486] MASS (ES+): m/e 460 (M+1).

[1487] Preparation 297

[1488] To a stirred solution of Compound (254) (4.0 g) in DMF (40 mL)were added acrylic acid t-butyl ester (8.13 mL), palladium(II) acetate(125 mg), triphenylphosphine (583 mg) and N,N-diisopropylethylamine (3.2mL). The mixture was stirred at 100° C. for 1 hr. The resulting mixturewas poured into saturated aqueous NaHCO₃ solution and extracted withAcOEt. The organic phase was washed with saturated aqueous NaHCO₃solution and brine, and dried over Na₂SO₄. The solvent was removed invacuo and purified by silica gel column chromatography eluted with AcOEtto give Compound (297) (2.56 g) as colorless solid.

[1489]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 4.18 (2H, s), 6.34 (1H,d, J=16.1 Hz), 7.21 (1H, s), 7.25 (1H, m), 7.28 (2H, d, J=8.4 Hz), 7.37(2H, t, J=7.4 Hz), 7.47 (2H, d, J=8.4 Hz), 7.55 (1H, d, J=16.1 Hz);

[1490] MASS (ES+): m/e 361 (M+1).

[1491] Preparation 298

[1492] To a solution of 4-iodophenol (1.0 g) in DMF (10 mL) was addedK₂CO₃ (powder 325 mesh, manufactured by Aldrich, 691 mg) was added, andthe mixture was stirred for 15 min. To the mixture was added ethyl4-bromobutanoate (0.722 mL), and the mixture was stirred for 65 hrs atambient temperature. The resulting mixture was poured into saturatedaqueous ammonium chloride solution and extracted with AcOEt. The organicphase was sequentially washed with water, saturated aqueous ammoniumchloride solution, water and brine, and dried over Na₂SO₄. The solventwas removed in vacuo, and residual colorless oil was purified by silicagel column chromatography eluting with AcOEt and hexane (1:4) to giveCompound (298) (1.32 g) as colorless oil.

[1493]¹H-NMR (300 MHz, CDCl₃, δ): 1.26 (3H, t, J=7.1 Hz), 2.10 (2H,quint., J=6.7 Hz), 2.50 (2H, t, J=7.3 Hz), 3.97 (2H, t, J=6.0 Hz), 4.14(2H, q, J=7.1 Hz), 6.66 (2H, d, J=9.2 Hz), 7.54 (2H, d, J=9.2 Hz);

[1494] MASS: Not Detected.

[1495] Preparation 299

[1496] Compound (299) was obtained from 4-iodophenol according to amanner similar to Preparation 298 (1.70 g).

[1497]¹H-NMR (300 MHz, CDCl₃, δ): 1.26 (3H, t, J=7.1 Hz), 1.81 (4H, m),2.38 (2H, m), 3.94 (2H, m), 4.14 (2H, q, J=7.2 Hz), 6.66 (2H, d, J=9.2Hz), 7.54 (2H, d, J=9.2 Hz);

[1498] MASS: Not Detected.

[1499] Preparation 300

[1500] To a solution of Compound (298) (1.32 g) in dioxane 13 mL wasadded 1N NaOH aq solution (11.9 mL) and the mixture was stirred for 15hrs. The organic solvent was removed in vacuo, and the pH value ofresidual aqueous phase was adjusted to 3 with 1N HCl. The precipitatewas collected by filtration and dried in vacuo to give Compound (300)(1.047 g) as colorless powder.

[1501]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.91 (2H, quint., J=6.8 Hz), 2.36(2H, t, J=7.3 Hz), 3.95 (2H, t, J=6.4 Hz), 6.78 (2H, d, J=8.9 Hz), 7.58(2H, d, J=9.2 Hz);

[1502] MASS (ES+): Not Detected.

[1503] Preparation 301

[1504] Compound (301) was obtained from Compound (299) according to amanner similar to Preparation 300 (883 mg).

[1505]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.56-1.76 (4H, m), 2.26 (2H, t,J=7.1 Hz), 3.94 (2H, t, J=6.2 Hz), 6.78 (2H, d, J=8.8 Hz), 7.57 (2H, d,J=8.8 Hz);

[1506] MASS: Not Detected.

[1507] Preparation 302

[1508] Compound (302) was obtained from Compound (300) according to amanner similar to Preparation 297 (1.026 g).

[1509]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 2.13 (2H, quint., J=6.6Hz), 2.58 (2H, t, J=7.2 Hz), 4.05 (2H, t, J=6.0 Hz), 6.24 (1H, d, J=15.8Hz), 6.87 (2H, d, J=8.8 Hz), 7.44 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=16.1Hz);

[1510] MASS Not Detected.

[1511] Preparation 303

[1512] Compound (303) was obtained from Compound (301) according to amanner similar to Preparation 297 (635 mg).

[1513]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 1.85 (4H, m), 2.45 (2H,t, J=5.9 Hz), 4.00 (2H, t, J=5.9 Hz), 6.24 (1H, d, J=16.1 Hz), 6.87 (2H,d, J=8.8 Hz), 7.44 (2H, d, J=8.8 Hz), 7.54 (1H, d, J=15.8 Hz);

[1514] MASS: Not Detected.

[1515] Preparation 304

[1516] Compound (304) was obtained from 4-(4-iodophenyl)butanoic acidaccording to a manner similar to Preparation 297 (1.68 mg).

[1517]¹H-NMR (300 MHz, CDCl₃, δ): 1.53 (9H, s), 1.97 (2H, quint., J=7.5Hz), 2.38 (2H, t, J=7.3 Hz), 2.69 (2H, t, J=7.5 Hz), 6.33 (1H, d, J=15.8Hz), 7.19 (2H, d, J=8.1 Hz), 7.44 (2H, d, J=8.1 Hz), 7.56 (2H, d, J=15.8Hz);

[1518] MASS: Not Detected.

[1519] Preparation 305

[1520] Compound (305) was obtained from Compound (318) described lateraccording to a manner similar to Preparation 297 (2.45 g).

[1521]¹H-NMR (300 MHz, CDCl₃, δ): 1.43 (1H, s), 1.53 (9H, s), 1.69 (1H,s), 1.93 (1H, s), 2.59 (1H, s), 6.33 (1H, d, J=16.4 Hz), 7.10 (2H, d,J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.55 (1H, d, J=15.8 Hz);

[1522] MASS (ES−): m/e 287 (M−1).

[1523] Preparation 306

[1524] To a solution of Compound (302) in DMF (3 mL) were addedtert-butyl 2-aminophenylcarbamate (224 mg), HOBt (172 mg) andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl,224 mg), and the mixture was stirred at ambient temperature for 2 hrs.The mixture was poured into saturated aqueous NaHCO₃ solution andextracted with ethyl acetate. The organic phase was sequentially washedwith saturated NH₄Cl solution, saturated NaHCO₃ solution and brine, anddried over Na₂SO₄. The solvent was removed in vacuo and the residue waspurified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (306) (379 mg) as paleyellow form.

[1525]¹H-NMR (300 MHz, CDCl₃, δ): 1.50 (9H, s), 1.53 (9H, s), 2.23 (2H,quint., J=6.6 Hz), 2.60 (2H, t, J=7.0 Hz), 4.09 (2H, t, J=6.0 Hz), 6.24(1H, d, J=15.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.16 (2H, m), 7.36 (1H, m),7.44 (2H, d, J=8.8 Hz), 7.50 (1H, m), 7.53 (1H, d, J=15.8 Hz);

[1526] MASS (ES+): m/e 497 (M+1).

[1527] Preparation 307

[1528] Compound (307) was obtained from Compound (303) according to amanner similar to Preparation 306 (395 mg).

[1529]¹H-NMR (300 MHz, CDCl₃, δ): 1.50 (9H, s), 1.53 (9H, s), 1.92 (4H,m), 2.47 (2H, m), 4.03 (2H, m), 6.24 (1H, d, J=16.1 Hz), 6.87 (2H, d,J=8.8 Hz), 7.17 (2H, m), 7.35 (1H, m), 7.44 (2H, d, J=8.8 Hz), 7.50 (1H,m), 7.53 (1H, d, J=16.1 Hz);

[1530] MASS (ES+): m/e 511 (M+1).

[1531] Preparation 308

[1532] Compound (308) was obtained from Compound (304) according to amanner similar to Preparation 306 (294 mg).

[1533]¹H-NMR (300 MHz, CDCl₃, δ): 1.48 (9H, s), 1.53 (9H, s), 2.07 (2H,quint., J=7.7 Hz), 2.40 (2H, t, J=7.9 Hz), 2.73 (2H, t, J=7.9 Hz), 6.33(1H, d, J=7.9 Hz), 7.18 (2H, m, J=16.1 Hz), 7.21 (2H, d), 7.35 (1H, m,J=8.1 Hz), 7.44 (2H, d), 7.50 (1H, m, J=8.1 Hz), 7.56 (1H, d, J=16.1Hz);

[1534] MASS (ES+): m/e 481 (M+1).

[1535] Preparation 309

[1536] To a stirred solution of Compound (306) (379 mg) in ACOH (4 mL)was added 1N HCl in AcOH (3.82 mL), and the mixture was heated at 120°C. for 2 hrs. The reaction mixture was cooled to ambient temperature anddiluted with AcOEt. The precipitate was collected by filtration to giveCompound (309) (199 mg) as pale yellow powder.

[1537]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.36 (2H, quint., J=6.5 Hz), 3.30(2H, t, J=7.5 Hz), 4.16 (2H, t, J=5.9 Hz), 6.37 (1H, d, J=16.1 Hz), 6.79(2H, d, J=8.4 Hz), 7.52 (1H, d, J=16.5 Hz), 7.55 (2H, m), 7.59 (2H, d,J=8.8 Hz), 7.79 (2H, m);

[1538] MASS (ES+): m/e 323 (M+1)

[1539] Preparation 310

[1540] Compound (310) was obtained from Compound (307) according to amanner similar to Preparation 309 (205 mg).

[1541]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.84 (2H, m), 2.03 (2H, m), 3.21(2H, t, J=7.6 Hz), 4.08 (2H, t, J=5.9 Hz), 6.38 (1H, d, J=16.1 Hz), 6.96(2H, d, J=8.8 Hz), 7.53 (2H, m), 7.54 (1H, d, J=15.8 Hz), 7.63 (2H, d,J=9.1 Hz), 7.78 (2H, m);

[1542] MASS (ES+): m/e 337 (M+1).

[1543] Preparation 311

[1544] Compound (311) was obtained from Compound (308) according to amanner similar to Preparation 309 (174 mg).

[1545]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.19 (2H, quint., J=7.1 Hz), 2.75(2H, t, J=7.3 Hz), 3.12 (2H, t, J=7.5 Hz), 6.48 (1H, d, J=16.1 Hz), 7.30(2H, d, J=7.7 Hz), 7.52 (2H, m), 7.56 (1H, d, J=15.0 Hz), 7.62 (2H, d,J=8.4 Hz), 7.76 (2H, m);

[1546] MASS (ES+): m/e 307 (M+1).

[1547] Preparation 312

[1548] To a stirred solution of Compound (309) (234 mg) in DMF (2 mL)was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (71.5 mg), HOBt(97.4 mg) and EDCI (112 mg), and the resulting mixture was stirred atambient temperature for 16 hrs. To the reaction mixture was addedsaturated aqueous NaHCO₃ solution, and the precipitate was collected byfiltration and washed with water. The obtained powder was dried in vacuoto give Compound (312) (161 mg) as colorless powder. The obtainedcompound (312) was used in Example 103.

[1549]¹H-NMR (300 MHz, CDCl₃, δ): 1.62 (3H, br.), 1.84 (3H, br.), 2.38(2H, quint., J=7.1 Hz), 3.13 (2H, t, J=7.1 Hz), 3.65 (1H, m), 3.98 (1H,m), 4.05 (2H, t, J=6.0 Hz), 5.02 (1H, s), 6.78 (2H, d, J=8.8 Hz), 7.23(2H, m), 7.37 (2H, d, J=8.4 Hz), 7.56 (2H, br.), 7.63 (1H, d, J=16.1Hz);

[1550] MASS (ES+): m/e 422 (M+1).

[1551] Preparation 313

[1552] Compound (313) was obtained from Compound (310) according to amanner similar to Preparation 312 (197 mg). The obtained compound (313)was used in Example 104.

[1553]¹H-NMR (300 MHz, CDCl₃, δ): 1.64 (3H, br.), 1.84 (3H, br.), 1.91(2H, m), 2.07 (2H, m), 3.01 (2H, t, J=7.7 Hz), 3.65 (1H, m), 3.97 (1H,m), 3.99 (2H, t, J=6.3 Hz), 5.02 (1H, s), 6.81 (2H, d, J=8.8 Hz), 7.22(2H, m), 7.40 (2H, d, J=8.1 Hz), 7.53 (2H, br.m), 7.67 (2H, d, J=15.0Hz);

[1554] MASS (ES+): m/e 436 (M+1).

[1555] Preparation 314

[1556] Compound (314) was obtained from Compound (311) according to amanner similar to Preparation 312 (177 mg). The obtained compound (314)was used in Example 105.

[1557]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 2.09(2H, quint., J=7.7 Hz), 2.69 (2H, t, J=7.7 Hz), 2.81 (2H, t, J=7.4 Hz),3.55 (1H, m), 3.96 (1H, m), 4.91 (1H, s), 6.47 (1H, d, J=16.1 Hz), 7.10(2H, m), 7.29 (2H, d, J=8.1 Hz), 7.46 (1H, d, J=15.8 Hz), 7.47 (2H, m),7.51 (2H, d, J=7.7 Hz);

[1558] MASS (ES+): m/e 406 (M+1).

[1559] Preparation 315

[1560] Compound (315) was obtained from Compound (320) described lateraccording to a manner similar to Preparation 312 (287 mg).

[1561]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.52 (3H, br.), 1.66 (1H, m), 1.69(3H, br.), 1.82 (1H, m), 2.40 (1H, m), 2.56 (1H, m), 3.50 (1H, m), 3.95(1H, m), 4.90 (1H, s), 6.47 (1H, d, J=15.8 Hz), 7.11 (2H, m) 7.25 (2H,d, J=8.1 Hz), 7.41 (1H, d, J=16.1 Hz), 7.44 (2H, m), 7.50 (2H, d, J=8.8Hz);

[1562] MASS (ES+): m/e 404 (M+1).

[1563] Preparation 316

[1564] Compound (316) was obtained from Compound (335) described lateraccording to a manner similar to Preparation 312 (55 mg). The obtainedcompound (316) was used in Example 100.

[1565]¹H-NMR (300 MHz, CDCl₃, δ): 1.60-1.90 (6H, m), 3.64-3.73 (1H, m),3.80 (3H, s), 3.94-4.04 (1H, m), 4.13 (2H, s), 4.82 (2H, s), 4.97-5.07(1H, m), 6.81-7.31 (8H, m), 7.45 (2H, d, J=8 Hz), 7.71 (1H, d, J=16 Hz);

[1566] MASS (ES+): m/z 516 (M+1).

[1567] Preparation 317

[1568] Compound (317) was obtained from Compound (202) according to amanner similar to Preparation 312 (177 mg). The obtained compound (317)was used in Example 101.

[1569]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.49-2.02 (21H, m), 3.49-3.58 (1H,m), 3.88-4.01 (3H, m), 4.87-4.93 (1H, m), 6.45 (1H, d, J=16 Hz), 7.18(1H, d, J=8 Hz), 7.26 (2H, d, J=8 Hz), 7.41-7.53 (3H, m).

[1570] MASS (ES+): m/z 462 (M+1)

[1571] Preparation 318

[1572] To a stirred solution of trans-2-phenylcyclopropanecarboxylicacid (5.0 g) in acetic acid (30 mL) were added periodic acid (3.13 g),iodine (3.13 g) and concentrated sulfuric acid (3.62 mL), and themixture was stirred at 75° C. for 5 hrs. The resulting mixture waspoured into 5% aqueous NaHSO₃ solution (100 mL), and the precipitate wascollected by filtration. The filtrate was extracted with AcOEt, and theorganic phase was sequentially washed with 5% aqueous NaHSO₃ solution,saturated aqueous NH₄Cl solution and brine, and dried over Na₂SO₄. Thesolvent was removed in vacuo, and the residual solid was combined withthe powder obtained by filtration, and dissolved in AcOEt. Theprecipitate was filtered off, and the filtrate was concentrated andcrystallized from ethyl acetate and hexane (20 mL: 40 mL) to giveCompound (318) (3.88 g).

[1573]¹H-NMR (300 MHz, CDCl₃, δ): 1.36 (1H, m), 1.66 (1H, m), 1.87 (1H,m), 2.53 (1H, m), 6.86 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz);

[1574] MASS (ES−): m/e 287 (M−1).

[1575] Preparation 319

[1576] To a solution of Compound (305) (500 mg) in DMF (5 mL) were added1,2-benzenediamine (206 mg), HOBt (305 mg) and EDCI.HCl (432 mg), andthe mixture was stirred for 2 hrs at ambient temperature. The mixturewas poured into saturated aqueous NaHCO₃ solution and extracted withAcOEt. The organic phase was sequentially washed with saturated aqueousNaHCO₃ solution, water and brine, and dried over Na₂SO₄. The solvent wasremoved in vacuo, and the residue was purified by preparative thin layerchromatography (chloroform:methanol=10:1). The obtained amorphous solidwas triturated with isopropyl ether to give Compound (319) (341 mg) ascolorless powder.

[1577]¹H-NMR (300 MHz, CDCl₃, δ): 1.40 (1H, m), 1.53 (9H, s), 1.77 (1H,m), 1.84 (1H, m), 2.62 (1H, m), 3.85 (1H, br.), 6.34 (1H, d, J=15.8 Hz),6.80 (2H, m), 7.07 (2H, m), 7.13 (2H, d, J=8.4 Hz), 7.34 (2H, s), 7.45(2H, d, J=8.4 Hz), 7.56 (1H, d, J=16.1 Hz);

[1578] MASS (ES+): m/e 379 (M+1).

[1579] Preparation 320

[1580] A solution of Compound (319) (341 mg) in AcOH (3.5 mL) was added1N-hydrogen chloride in AcOH (3.6 mL) was heated at 110° C. for 2 hr.The resulting mixture was allowed to cool to ambient temperature,diluted with ethyl acetate. The precipitate was collected by filtrationand dried to give Compound (320) (242 mg).

[1581]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.03 (1H, m), 2.14 (1H, m), 2.70(1H, m), 2.92 (1H, m), 6.53 (1H, d, J=15.8 Hz), 7.35 (2H, d, J=8.4 Hz),7.49 (2H, m), 7.58 (1H, d, J=16.1 Hz), 7.68 (2H, d, J=8.1 Hz), 7.73 (2H,m);

[1582] MASS (ES+): m/e 305 (M+1).

[1583] Preparation 321

[1584] To a stirred solution of Compound (217) (350 mg) in methanol (3mL) was added 1N sodium hydroxide (1.65 mL) in an ice bath. After 1 hr,the mixture was allowed to warm to ambient temperature and stirred atthe same temperature for 16 hrs. To this mixture was added concentratedhydrochloric acid to acidify the mixture, and the resulting mixture wasconcentrated in vacuo. The residue was dissolved inN,N-dimethylformamide (5 mL), and to this solution were successivelyadded O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (167 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (222 mg) and1-hydroxybenzotriazole (193 mg) at ambient temperature. The resultingmixture was stirred at the same temperature for two days, extracted withethyl acetate (100 mL), and successively washed with saturated aqueoussodium bicarbonate (25 mL) and brine (25 mL). The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel flash chromatography eluting with amixture of methanol and ethyl acetate (5:95 v/v) to afford Compound(321) (387 mg) as a colorless amorphous solid. The obtained Compound(321) was used in Example 82.

[1585]¹H-NMR (300 MHz, CDCl₃, δ): 1.43-1.82 (6H, m), 3.43-3.59 (1H, m),3.84-4.07 (1H, m), 4.89 (1H, br.s), 5.36 (2H, s), 6.47 (1H, d, J=16.1Hz), 7.00-7.09 (3H, m), 7.33-7.59 (10H, m);

[1586] MASS (ES+): m/z 404 (M+1)

[1587] Preparation 322

[1588] Compound (322) was obtained as a mixture of two regioisomers fromCompound (218) according to a manner similar to Preparation 321 (316 mgin total). The obtained Compound (322) was used in Example 115.

[1589]¹H-NMR (300 MHz, DMSO-d₆, δ): (for a mixture of two regioisomers)1.34-1.78 (6H, m), 2.03 (1.2H, s), 2.06 (1.8H, s), 3.47-3.59 (1H, m),3.85-4.04 (1H, m), 4.83-4.95 (1H, m), 5.13 (1.2H, s), 5.19 (0.8H, s),6.49 (1H, d, J=16.4 Hz), 6.67 (0.4H, s), 6.85 (0.6H, s), 7.13 (0.8H, d,J=8.1 Hz), 7.26 (1.2H, d, J=8.1 Hz), 7.39-7.72 (4H, m);

[1590] MASS (ES+): (for a mixture of two regioisomers) m/z 342 (M+1).

[1591] Preparation 323

[1592] To a stirred solution of Compound (326) (100 mg, described laterin Preparation 326) in N,N-dimethylformamide (2 mL) were addedmethylamine hydrochloride (23 mg),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (56 mg) and1-hydroxybenzotriazole (48 mg) at ambient temperature, and the resultingmixture was stirred at the same temperature for 20 hrs. The mixture wasextracted with ethyl acetate (50 mL), and successively washed withsaturated aqueous sodium bicarbonate (25 mL) and brine (25 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo to afford crude Compound (324) (86 mg) as a colorless amorphoussolid. The Compound (324) was used in Example 83.

[1593]¹H-NMR (300 MHz, CDCl₃, δ): 1.42-1.97 (6H, m), 2.85 (3H, br.d,J=4.4 Hz), 3.54-3.68 (1H, m), 3.89-4.07 (2H, m), 4.98 (2H, br.s),6.05-6.34 (1H, m), 6.95-7.73 (10H, m);

[1594] MASS (ES+): m/z 461 (M+1).

[1595] Preparation 324

[1596] To a solution of Compound (326) (60 mg, described later inPreparation 326) in DMF (1 mL) were added piperidine (0.015 mL), HOBt(23.6 mg) and EDCI HCl (33.4 mg), and the mixture was stirred for 2 hrsat ambient temperature. The mixture was poured into water and extractedwith AcOEt, and the organic phase was sequentially washed with saturatedaqueous NH₄Cl solution, saturated aqueous NaHCO₃ solution and brine, anddried over Na₂SO₄. The solvent was removed in vacuo, and the residue waspurified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (324) (44 mg) as colorlessamorphous solid. The obtained Compound (324) was used in Example 88.

[1597]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.25 (2H, br.), 1.53 (7H, br.), 1.69(3H, br.), 3.25 (4H, br.), 3.53 (1H, m), 3.94 (1H, m), 4.03 (2H, s),4.90 (1H, s), 6.46 (1H, d, J=15.4 Hz), 7.26 (1H, t, J=7.3 Hz), 7.36 (4H,m), 7.43 (1H, d, J=15.8 Hz), 7.53 (4H, m);

[1598] MASS (ES+): m/e 515 (M+1).

[1599] Preparation 325

[1600] Compound (325) was obtained from Compound (326) described lateraccording to a manner similar to Preparation 325 (57 g). The obtainedcompound (325) was used in Example 89.

[1601]¹H-NMR (300 MHz, CDCl₃, δ): 1.18 (6H, br.), 1.60 (3H, br.), 1.84(3H, br.), 3.65 (1H, m), 3.98 (1H, m), 4.09 (2H, s), 4.18 (1H, m), 5.00(1H, s), 7.22 (1H, m), 7.39 (6H, m), 7.67 (3H, m);

[1602] MASS (ES+): m/e 489 (M+1).

[1603] Preparation 326

[1604] To a solution of Compound (290) (200 mg) in dioxane (2 mL) wasadded 1N NaOH aqueous solution (1.3 mL) and the mixture was heated at70° C. for 6 hrs. The organic solvent was removed in vacuo and the pHvalue of aqueous base adjusted to 3 with 1N HCl. The precipitate wascollected by filtration and dried to give Compound (326) (145 mg) aspale yellow powder. The obtained Compound (326) was used in Example 91.

[1605]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.53(1H, m), 3.95 (1H, m), 4.05 (2H, s), 4.90 (1H, s), 6.46 (1H, d, J=16.4Hz), 7.32-7.40 (5H, m), 7.46 (1H, d, J=16.1 Hz), 7.53 (2H, d, J=7.7 Hz),7.86 (2H, br);

[1606] MASS (ES+): m/e 448 (M+1).

[1607] Preparation 327

[1608] To a suspension of lithium aluminum hydride in THF (5 mL) wasadded a solution of Compound (290) (500 mg) in THF (5 mL) and themixture was refluxed for 6 hrs. To the resulting solution was addedwater (50 mL) at ambient temperature, and the mixture was stirred for 1hr. The precipitate was collected by filtration, and the obtained powderwas purified by silica gel column chromatography eluting with a mixtureof chloroform and methanol (10:1) to give Compound (327) (110 mg).

[1609]¹H-NMR (300 MHz, CDCl₃, δ): 1.54 (9H, s), 3.68 (2H, s), 3.88 (3H,s), 4.69 (2H, d, J=4.0 Hz), 6.37 (1H, d, J=15.8 Hz), 6.60 (1H, br), 6.95(2H, d, J=8.8 Hz), 7.33 (2H, d, J=8.1 Hz), 7.52 (2H, d, J=8.1 Hz), 7.58(1H, d, J=16.1 Hz), 7.91 (2H, d, J=9.2 Hz);

[1610] MASS (ES+): m/e 434 (M+1).

[1611] Preparation 328

[1612] Compound (328) was obtained from Compound (50) according to amanner similar to Preparation 327 (493 mg). The obtained compound (328)was used in Example 97.

[1613]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.48-1.72 (6H, m), 3.49-3.57 (1H,m), 3.90-4.01 (1H, m), 4.18 (2H, s), 4.51-4.58 (2H, m), 4.87-4.92 (1H,m), 6.47 (1H, d, J=16 Hz), 7.33-7.57 (8H, m);

[1614] MASS (ES+): m/z 408 (M+1).

[1615] Preparation 329

[1616] To a suspension of Compound (327) (400 mg) in dichloromethane (3mL) was added triethylamine (0.154 mL) and methanesulfonyl chloride(0.079 mL) at 5° C., and the mixture was stirred for 1 hr. The solventwas removed in vacuo, and the obtained benzyl chloride was dissolved inMeOH. To the solution was added sodium methoxide in MeOH (5 equivalent)at ambient temperature, and the mixture was stirred for 0.5 hr. Theresulting mixture was poured into saturated aqueous NH₄Cl solution andextracted with AcOEt. The organic phase was washed with water and brine,and dried over Na₂SO₄. The solvent was removed in vacuo, and the residuewas purified by preparative thin layer chromatography(chloroform:methanol=10:1) to give Compound (329) (110 mg). The obtainedcompound (329) was used in Example 93.

[1617]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 3.29(3H, s), 3.53 (1H, m), 3.97 (1H, m), 4.05 (2H, s), 4.39 (2H, s), 4.90(1H, s), 6.47 (1H, d, J=15.8 Hz), 7.25-7.61 (10H, m);

[1618] MASS (ES+): m/e 448 (M+1).

[1619] Preparation 330

[1620] To a solution of Compound (323) (1 g) in DMF (5 mL) were addedN,O-dimethylhydroxylamine hydrochloride (240 mg) and HOBt (393 mg) andEDCI (451 mg), and the mixture was stirred at ambient temperature. Tothe resulting mixture was added saturated aqueous NaHCO₃ solution, andthe precipitate was collected by filtration. The obtained powder waswashed with water and Et₂O to give Compound (330) (817 mg) as paleyellow powder.

[1621]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.53 (3H, br.), 1.69 (3H, br.), 3.21(3H, s), 3.53 (1H, m), 3.63 (3H, s), 3.95 (1H, m), 4.05 (2H, s), 4.90(1H, s), 6.46 (1H, d, J=16.1 Hz), 7.30-7.60 (10H, m);

[1622] MASS (ES+): m/z 491 (M+1).

[1623] Preparation 331

[1624] To a solution of Compound (330) (300 mg) in THF (5 mL) was addedmethyl magnesium iodide in Et₂O (3.64 mL, 0.84 mol/L, Kanto Chemical,Co., Inc.) and the mixture was heated at 70° C. for 3 hrs.Methylmagnesium iodide in Et₂O (0.84 mol/L, 3.64 mL) was then addedthereto, and the mixture was additionally heated at 70° C. for 2 hrs.The mixture was cooled, poured into water and extracted with AcOEt. Theorganic phase was successively washed with saturated aqueous NaHCO₃solution, water and brine, and dried over Na₂SO₄. The solvent wasremoved in vacuo, and the residue was purified by preparative thin layerchromatography (chloroform:methanol=10:1) to give Compound (331) (67 mg)as orange form. The obtained Compound (331) was used in Example 94.

[1625]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.54 (3H, br.), 1.69 (3H, br.), 2.36(3H, s), 3.55 (1H, m), 3.95 (1H, m), 4.22 (2H, s), 4.90 (1H, s), 6.48(1H, d, J=15.8 Hz), 7.31-7.57 (10H, m);

[1626] MASS (ES+): m/z 446 (M+1).

[1627] Preparation 332

[1628] Compound (332) was obtained from Compound (326) according to amanner similar to Preparation 330 (124 mg). The obtained compound (332)was used in Example 87.

[1629] Preparation 333

[1630] To a solution of Compound (51) (120 mg), pyrrolidine (0.029 mL)and 1-hydroxybenzotriazole (46.2 mg) in N,N-dimethylformamide (2.6 mL)was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (65.5 mg) at 4°C. The mixture was warmed to ambient temperature and stirred for 8 hrs.The reaction mixture was added saturated NaHCO₃ (3 mL) and water (12mL). A resulting precipitate was collected by filtration, and washedwith water to give Compound (333) (95 mg).

[1631]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.47-1.93 (10H, m), 3.39-3.57 (5H,m), 3.87-4.01 (1H, m), 4.22 (2H, s), 4.88-4.93 (1H, m), 6.47 (1H, d,J=16 Hz), 7.28-7.70 (8H, m);

[1632] MASS (ES+): m/z 475 (M+1)

[1633] Preparation 334

[1634] To a mixture of Compound (328) (170 mg),N,N-diisopropylethylamine (0.16 mL) and THF (8.4 mL) was addedmethanesulfonyl chloride (0.068 mL) at 4° C. The reaction mixture wasstirred for 3 hrs and diethylamine (0.432 mL) was added thereto. Afterstirring for 15 hrs at room temperature, the resulting mixture waspartitioned between ethyl acetate and H₂O. The organic layer was washedwith saturated NaHCO₃ and brine, dried over MgSO₄, filtered andevaporated in vacuo to give Compound (334) (38 mg).

[1635]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.03-1.22 (6H, m), 1.48-1.72 (6H, m)3.31-3.44 (4H, m), 3.49-3.57 (1H, m), 3.88-4.03 (1H, m), 4.10-4.41 (4H,m), 4.87-4.95 (1H, m), 6.48 (1H, d, J=16 Hz), 7.22-7.87 (8H, m).

[1636] MASS (ES+): m/z 463 (M+1).

[1637] Preparation 335

[1638] Compound (335) was obtained from Compound (6) according tomanners similar to Preparations 199 and 229 (2.89 g).

[1639]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7 Hz), 3.64-4.08 (7H,m), 4.27 (2H, q, J=7 Hz), 4.53-4.64 (2H, m), 6.42 (1H, d, J=16 Hz),6.81-6.92 (2H, m), 7.01 (1H, d, J=8 Hz), 7.27-7.35 (3H, m), 7.45-7.53(2H, m), 7.66 (1H, d, J=16 Hz);

[1640] MASS (ES−): m/z 410 (M−1)

[1641] Preparation 336

[1642] To a mixture of Compound (335) (1.44 g) in chloroform (12 mL) wasadded trifluoroacetic anhydride (1.48 mL) at 4° C. After stirring for 3hrs at room temperature, the reaction mixture was evaporated in vacuo.To a mixture of the above product in N,N-dimethylformamide (18 mL) wasadded ammonium acetate (405 mg) at 4° C. After stirring at 70° C. for 2hrs, the resulting mixture was partitioned between ethyl acetate andH₂O. The organic layer was washed with H₂O and brine, dried over MgSO₄,filtered and evaporated in vacuo. To a mixture of the above product inpyridine (1 mL) was added phosphorus oxychloride (0.3 mL) at 4° C. Afterstirring at 90° C. for 2 hrs, the resulting mixture was partitionedbetween ethyl acetate and H₂O. The organic layer was washed with H₂O andbrine, dried over MgSO₄, filtered and evaporated in vacuo. The residuewas purified by column chromatography on silica gel to give Compound(336) (313 mg).

[1643]¹H-NMR (300 MHz, CDCl₃, δ): 1.34 (3H, t, J=7 Hz), 3.79 (3H, s)4.12 (2H, s), 4.19 (2H, q, J=7 Hz), 4.81 (2H, s), 6.41 (1H, d, J=16 Hz),6.81-6.90 (4H, m), 7.11-7.19 (3H, m), 7.45 (2H, d, J=8 Hz), 7.65 (1H, d,J=16 Hz);

[1644] MASS (ES+): m/z 445 (M+1).

[1645] Preparation 337

[1646] To a mixture of Compound (336) (175 mg) in dioxane (4 mL) wasadded 1N sodium hydroxide (1.18 mL). After stirring at 80° C. for 1 hr,the reaction mixture was added H₂O (20 mL) and acidified with 1Nhydrochloric acid (to pH 3-4). The resulting precipitate was collectedby filtration and washed with H₂O to give Compound (337) (153 mg).

[1647]¹H-NMR (300 MHz, CDCl₃, δ): 3.79 (3H, s), 4.14 (2H, s), 4.82 (2H,s), 6.42 (1H, d, J=16 Hz), 6.81-6.91 (4H, m), 7.11-7.21 (3H, m), 7.48(2H, d, J=8 Hz), 7.73 (1H, d, J=16 Hz);

[1648] MASS (ES−): m/z 415 (M−1)

[1649] Preparation 338

[1650] To a mixture of (1Z)-2-(4-iodophenyl)-N′-hydroxyethaneimidamide(2.17 g) in EtOH (40 mL) was added ethyl propiolate (0.803 mL), and themixture was heated under reflux for 6 hrs. The reaction mixture wasevaporated in vacuo. The residue was added diphenylether (20 mL) andstirred at 200° C. for 2 hrs. After cooling, the resulting mixture waspurified by column chromatography on silica gel (eluting with CHCl₃:MeOH=50:1) to give Compound (338) (845 mg).

[1651]¹H-NMR (300 MHz, CDCl₃, δ): 1.30-1.43 (3H, m), 4.06-4.13 (2H, m),4.26-4.43 (2H, m), 6.97-7.06 (2H, m), 7.61 (1H, s), 7.65-7.72 (2H, m);

[1652] MASS (ES+): m/z 357 (M+1).

[1653] Preparation 339

[1654] To a solution of Compound (338) (400 mg), palladium(II) acetate(12.6 mg) and triphenylphosphine (29.5 mg) in DMF (11 mL) were addedacrylic acid (0.154 mL) and N,N-diisopropylethylamine (0.49 mL), and themixture was stirred at 70° C. for 6 hrs. The reaction mixture waspartitioned between ethyl acetate and H₂O, and the inorganic layer wasevaporated in vacuo. To a mixture of the obtained reaction product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (1.5 eq.) and1-hydroxybenzotriazole (1.5 eq.) in N,N-dimethylformamide (6 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.5 eq.) at 4° C.The mixture was warmed to ambient temperature and stirred for 6 hrs. Tothe reaction mixture were added saturated NaHCO₃ (6 mL) and water (24mL), and the mixture was extracted with ethyl acetate. The organic layerwas washed with H₂O and brine, dried over MgSO₄, filtered and evaporatedin vacuo. The residue was purified by column chromatography on silicagel to give Compound (339) (98 mg).

[1655]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.25 (3H, t, J=7 Hz), 1.44-1.75 (6H,m), 3.45-3.59 (1H, m), 3.88-4.01 (1H, m) 4.01 (2H, s), 4.18 (2H, q, J=7Hz), 4.87-4.93 (1H, m), 6.46 (1H, d, J=16 Hz), 7.24-7.78 (5H, m), 8.32(1H, s);

[1656] MASS (ES+): m/z 400 (M+1)

[1657] Preparation 340

[1658] Compound (340) was obtained according to manners similar toPreparations 319 and 320 (184 mg).

[1659]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.95-2.08 (4H, m), 3.22-3.34 (4H,m), 4.50 (2H, s), 6.55 (1H, d, J=16 Hz), 6.62 (1H, s), 6.84 (1H, dd,J=2, 8 Hz), 7.48-7.75 (6H, m);

[1660] MASS (ES+): m/z 348 (M+1).

EXAMPLE 1

[1661] To a stirred solution of Compound (5) (125 mg) in methanol (5 mL)was added hydrogen chloride methanol reagent 10 (0.5 mL, manufactured byTokyo Kasei Kogyo Co., Ltd.), and the mixture was stirred at ambienttemperature for 30 minutes. The solvent was evaporated in vacuo and theresidue was triturated with the mixture of methanol and ethyl acetate(1:2) to give Compound E1 as a white solid (81 mg).

[1662]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.57 (2H, s), 6.50 (1H, d, J=15.7Hz), 7.41-7.56 (5H, m), 7.60 (2×1H, d, J=8 Hz), 7.73-7.81 (2H, m), 10.84(1H, br);

[1663] MASS (ES+): m/e 294.

EXAMPLE 2

[1664] Compound E2 was obtained from Compound (13) according to a mannersimilar to Example 1 (79 mg).

[1665]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.76 (2H, s), 5.82 (2H, s), 6.49(1H, d, J=16 Hz), 7.12-7.21 (2H, m), 7.26-7.34 (3H, m), 7.38-7.62 (7H,m), 7.73 (1H, dd, J=7, 1.5 Hz), 7.83 (1H, dd, J=7, 1.5 Hz);

[1666] MASS (ES+): m/e 384.

EXAMPLE 3

[1667] Compound E3 was obtained from Compound (19) according to a mannersimilar to Example 1 (1.74 mg).

[1668]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.28 (2×1H, t, J=7.5 Hz), 3.47(2×1H, t, J=7.5 Hz), 6.45 (1H, d, J=16 Hz), 7.32 (2×1H, d, J=8 Hz), 7.41(1H, d, J=16 Hz), 7.46-7.60 (4H, m), 7.73-7.83 (2H, m), 10.80 (1H, s),15.10 (1H, br);

[1669] MASS (ES+): m/e 308.

EXAMPLE 4

[1670] Compound E4 was obtained from Compound (22) according to a mannersimilar to Example 1 (377 mg).

[1671]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.79 (2H, s), 6.50 (1H, d, J=16 Hz),7.43 (1H, d, J=16 Hz), 7.48-7.64 (6H, m), 7.86-7.94 (2H, m), 9.84 (1H,s);

[1672] MASS (ES+): m/e 294.

EXAMPLE 5

[1673] Compound E5 was obtained from Compound (25) according to a mannersimilar to Example 1 (102 mg).

[1674]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.31 (1H, m), 3.70 (1H, dd, J=13, 8Hz), 4.74 (1H, br-t, J=8 Hz), 5.34 (1H, d, J=17 Hz), 5.41 (1H, d, J=17Hz), 6.37 (1H, d, J=15.5 Hz), 6.73 (2×1H, d, J=6.5 Hz), 7.07-7.45 (16H,m), 7.71 (1H, d, J=7.5 Hz), 9.02 (1H, brs), 10.73 (1H, brs);

[1675] MASS (ES+): m/e 474.

EXAMPLE 6

[1676] Compound E6 was obtained from Compound (29) according to a mannersimilar to Example 1 (1.88 mg).

[1677]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.57 (2H, s), 6.51 (1H, d, J=16 Hz),7.40-7.56 (6H, m), 7.68 (1H, s), 7.73-7.81 (2H, m), 10.88 (1H, s);

[1678] MASS (ES+): m/e 294.

EXAMPLE 7

[1679] Compound E7 was obtained from Compound (32) according to a mannersimilar to Example 1 (162 mg).

[1680]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.50 (1H, d, J=15.7Hz), 7.38-7.56 (6H, m), 7.61 (2×1H, d, J=8 Hz), 7.73 (2×1H, d, J=7 Hz),7.78-7.88 (2H, m), 7.96 (1H, s), 10.84 (1H, s);

[1681] MASS (ES+): m/e 370.

EXAMPLE 8

[1682] Compound E8 was obtained from Compound (34) according to a mannersimilar to Example 1 (75 mg).

[1683]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.50 (2H, s), 6.48 (1H, d, J=16 Hz),7.42-7.48 (3H, m), 7.56-7.71 (4H, m), 7.97 (1H, d, J=2 Hz);

[1684] MASS (ESI): m/z 372 (M+1)

EXAMPLE 9

[1685] Compound E9 was obtained from Compound (35) according to mannerssimilar to Preparation 9 and Example 1 (152 mg).

[1686]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.63 (3H, s), 4.58 (2H, s), 6.49(1H, d, J=16 Hz), 7.46 (1H, d, J=16 Hz), 7.50 (2H, d, J=8 Hz), 7.61 (2H,d, J=8 Hz), 7.85-7.93 (4H, m), 8.04-8.10 (3H, m);

[1687] MASS (ESI): m/z 412 (M+1)

EXAMPLE 10

[1688] Compound E10 was obtained from Compound (36) according to mannerssimilar to Preparation 9 and Example 1 (138 mg).

[1689]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.50 (1H, d, J=16 Hz),7.17-7.21 (1H, m), 7.46 (1H, d, J=16 Hz), 7.51 (2H, d, J=8 Hz),7.59-7.65 (4H, m), 7.80-7.83 (2H, m), 7.95 (1H, s);

[1690] MASS (ESI): m/z 376 (M+1).

EXAMPLE 11

[1691] Compound E11 was obtained from Compound (37) according to mannerssimilar to Preparation 9 and Example 1 (120 mg).

[1692]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.49 (1H, d, J=16 Hz),7.46 (1H, d, J=16 Hz), 7.51 (2H, d, J=8 Hz), 7.61 (2H, d, J=8 Hz),7.64-7.73 (2H, m), 7.79 (1H, d, J=8 Hz), 7.90 (1H, dd, J=2, 8 Hz),8.00-8.05 (2H, m);

[1693] MASS (ESI): m/z 376 (M+1).

EXAMPLE 12

[1694] Compound E12 was obtained from Compound (39) according to amanner similar to Example 1 (142 mg).

[1695]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.42 (2H, s), 6.46 (1H, d, J=16 Hz),7.41-7.47 (3H, m), 7.56 (2H, d, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.80 (1H,d, J=8 Hz), 8.22 (1H, s);

[1696] MASS (ESI): m/z 317 (M−1).

EXAMPLE 13

[1697] Compound E13 was obtained from Compound (40) according to mannerssimilar to Preparation 9 and Example 1 (710 mg).

[1698]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.55 (2H, s), 6.50 (1H, d, J=16 Hz),7.36-7.44 (1H, m), 7.45 (1H, d, J=16 Hz), 7.50 (2H, d, J=8 Hz), 7.59(2H, d, J=8 Hz), 7.66 (1H, dd, J=2, 8 Hz), 7.77-7.83 (1H,

[1699] MASS (ESI): m/z 312 (M+1].

EXAMPLE 14

[1700] Compound E14 was obtained from Compound (42) according to amanner similar to Example 1 (504 mg).

[1701]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.51 (2H, s), 6.48 (1H, d, J=16 Hz),7.45 (1H, d, J=16 Hz), 7.47 (2H, d, J=8 Hz), 7.52 (1H, dd, J=2, 8 Hz),7.59 (2H, d, J=8 Hz), 7.76 (1H, d, J=8 Hz), 7.86 (1H, J=2 Hz);

[1702] MASS (ESI): m/z 328 (M+1)

EXAMPLE 15

[1703] Compound E15 was obtained from Compound (44) according to amanner similar to Example 1 (14 mg).

[1704]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.79-2.85 (4H, m), 3.11-3.22 (4H,m), 4.52 (2H, s), 6.48 (1H, d, J=16 Hz), 7.15-7.67 (8H, m);

[1705] MASS (ESI): m/z 392 (M+1)

EXAMPLE 16

[1706] Compound E16 was obtained from Compound (46) according to amanner similar to Example 1 (45 mg).

[1707]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.15-3.21 (4H, m), 3.75-3.81 (4H,m), 4.52 (2H, s), 6.49 (1H, d, J=16 Hz), 7.10 (1H, d, J=2 Hz), 7.29 (1H,dd, J=2, 8 Hz), 7.42-7.50 (3H, m), 7.57-7.64 (3H, m);

[1708] MASS (ESI): m/z 379 (M+1).

EXAMPLE 17

[1709] Compound E17 was obtained from Compound (48) according to amanner similar to Example 1 (27 mg).

[1710]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.60-1.70 (2H, m), 1.83-2.00 (4H,m), 3.39-3.54 (4H, m), 4.54 (2H, s), 6.49 (1H, d, J=16 Hz), 7.40-7.86(8H, m);

[1711] MASS (ESI): m/z 377 (M+1)

EXAMPLE 18

[1712] A mixture of Compound (39), sodium azide (485 mg) andtriethylamine hydrochloride (1.54 g) in N,N-dimethylformamide (7.5 mL)was heated at 130° C. for 6 hours. After cooling, the reaction mixturewas partitioned between ethyl acetate (20 mL) and water (40 mL). Theorganic layer was washed with brine, dried over MgSO₄, filtered, andevaporated in vacuo. The crude product was triturated with ethylacetate-water. The product was treated according to a manner similar toExample 1 to give Compound E18 (18 mg).

[1713]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.30 (2H, s), 6.44 (1H, d, J=16 Hz),7.40 (2H, d, J=8 Hz), 7.44 (1H, d, J=16 Hz), 7.55 (2H, d, J=8 Hz), 7.72(1H, d, J=8 Hz), 7.90 (1H, d, J=8 Hz), 8.21 (1H, s);

[1714] MASS (ESI): m/z 362 (M+1)

EXAMPLE 19

[1715] Compound E19 was obtained from Compound (50) according to amanner similar to Example 1 (101 mg).

[1716]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.91 (3H, s), 4.55 (2H, s), 6.49(1H, d, J=16 Hz), 7.46 (1H, d, J=16 Hz), 7.50 (2H, d, J=8 Hz), 7.60 (2H,d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.27 (1H, s);

[1717] MASS (ESI): m/z 352 (M+1).

EXAMPLE 20

[1718] Compound E20 was obtained from Compound (51) according to amanner similar to Example 1 (72 mg).

[1719]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.55 (2H, s), 6.49 (1H, d, J=16 Hz),7.45 (1H, d, J=16 Hz), 7.49 (2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.81(1H, d, J=8 Hz), 8.04 (1H, dd, J=2, 8 Hz), 8.25 (1H, s);

[1720] MASS (ESI): m/z 338 (M+1)

EXAMPLE 21

[1721] Compound E21 was obtained from Compound (53) according to amanner similar to Example 1 (55 mg).

[1722]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.68 (3H, s), 4.56 (2H, s), 6.49(1H, d, J=16 Hz), 7.45 (1H, d, J=16 Hz), 7.50 (2H, d, J=8 Hz), 7.59 (2H,d, J=8 Hz), 7.83 (1H, d, J=8 Hz), 8.06 (1H, dd, J=2, 8 Hz), 8.28 (1H,s);

[1723] MASS (ESI): m/z 336 (M+1).

EXAMPLE 22

[1724] Compound E22 was obtained from Compound (55) according to amanner similar to Example 1 (279 mg).

[1725]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.48 (2H, s), 6.47 (1H, d, J=16 Hz),7.33-7.49 (4H, m), 7.57 (2H, d, J=8 Hz), 7.65-7.72 (4H, m);

[1726] MASS (ESI): m/z 372 (M+1).

EXAMPLE 23

[1727] Compound E23 was obtained from Compound (57) according to amanner similar to Example 1 (50 mg).

[1728]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.25 (3H, s), 1.27 (3H, s),3.04-3.16 (1H, m), 4.55 (2H, s), 6.49 (1H, d, J=16 Hz), 7.42-7.52 (4H,m), 7.56-7.62 (3H, m), 7.68 (1H, d, J=8 Hz);

[1729] MASS (ESI): m/z 336 (M+1).

EXAMPLE 24

[1730] Compound E24 was obtained from Compound (59) according to mannerssimilar to Preparation 9 and Example 1 (249 mg).

[1731]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.42 (2H, s), 5.35 (2H, s), 6.45(1H, d, J=16 Hz), 7.10-7.61 (13H, m);

[1732] MASS (ESI): m/z 400 (M+1).

EXAMPLE 25

[1733] Compound E25 was obtained from Compound (62) according to amanner similar to Example 1 (417 mg).

[1734]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.50 (1H, d, J=15.7Hz), 7.38-7.56 (6H, m), 7.61 (2×1H, d, J=8 Hz), 7.73 (2×1H, d, J=7 Hz),7.78-7.88 (2H, m), 7.96 (1H, s), 10.84 (1H, s);

[1735] MASS (ES+): m/e 370.

EXAMPLE 26

[1736] Compound E26 was obtained from Compound (72) according to amanner similar to Example 1 (207 mg).

[1737]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.57 (2H, s), 6.50 (1H, d, J=15.7Hz), 7.35 (2×1H, dd, J=8.8, 8.8 Hz), 7.46 (1H, d, J=15.7 Hz), 7.50(2×1H, d, J=8 Hz), 7.61 (2×1H, d, J=8 Hz), 7.74-7.86 (4H, m), 7.94 (1H,s);

[1738] MASS (ES+): m/e 388.

EXAMPLE 27

[1739] Compound E27 was obtained from Compound (75) according to amanner similar to Example 1 (123 mg).

[1740]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.58 (2H, s), 6.51 (1H, d, J=15.8Hz), 7.38-7.59 (7H, m), 7.65-7.87 (5H, m), 7.96 (1H, s), 10.86 (1H, br);

[1741] MASS (ES+): m/e 370.

EXAMPLE 28

[1742] Compound E28 was obtained from Compound (80) according to amanner similar to Example 1 (103 mg).

[1743]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.28 (3H, s), 4.59 (2H, s), 6.49(1H, d, J=16 Hz), 7.42-7.65 (5H, m), 7.87-7.92 (2H, m), 7.98-8.10 (5H,m);

[1744] MASS (ES+): m/e 447.

EXAMPLE 29

[1745] Compound E29 was obtained from Compound (83) according to amanner similar to Example 1 (200 mg).

[1746]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.49 (2H, s), 6.49 (1H, d, J=16 Hz),7.44 (1H, d, J=16 Hz), 7.47 (2×1H, d, J=8 Hz), 7.57 (2×1H, d, J=8 Hz),7.57 (1H, dd, J=8, 5 Hz), 8.34 (1H, d, J=8 Hz), 8.58 (1H, d, J=5 Hz);

[1747] MASS (ES+): m/e 295.

EXAMPLE 30

[1748] Compound E30 was obtained from Compound (90) according to amanner similar to Example 1 (175 mg).

[1749]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.52 (2H, s), 6.50 (1H, d, J=16 Hz),7.23 (1H, br-d, J=8.5 Hz), 7.41-7.53 (4H, m), 7.59 (2×1H, d, J=8 Hz),7.69 (1H, d, J=8.5 Hz);

[1750] MASS (ES+): m/e 309.

EXAMPLE 31

[1751] Compound E31 was obtained from Compound (93) according to amanner similar to Example 1 (14 mg).

[1752]¹H-NMR (300 MHz, DMSO-d₆, δ): 0.92 (3H, t, J=7.5 Hz), 1.63 (2H,tq, J=7.5, 7.5 Hz), 2.34 (2H, t, J=7.5 Hz), 4.54 (2H, s), 6.49 (1H, d,J=15.7 Hz), 7.41-7.51 (3H, m), 7.55 (1H, dd, J=9, 2 Hz), 7.60 (2×1H, d,J=8.5 Hz), 7.69 (1H, d, J=9 Hz), 8.31 (1H, d, J=2 Hz);

[1753] MASS (ES+): m/e 379.

EXAMPLE 32

[1754] Compound E32 was obtained from Compound (97) according to amanner similar to Example 1 (73 mg).

[1755]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.45 (2H, s), 6.45 (1H, d, J=16 Hz),7.43 (1H, d, J=16 Hz), 7.45 (2×1H, d, J=8 Hz), 7.50 (2×1H, dd, J=8, 8Hz), 7.54 (2×1H, d, J=8 Hz), 8.11 (1H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz);

[1756] MASS (ES+): m/e 339.

EXAMPLE 33

[1757] Compound E33 was obtained from Compound (100) according to amanner similar to Example 1 (15 mg).

[1758]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.43 (2H, s), 6.48 (1H, d, J=16 Hz),7.39-7.60 (5H, m), 8.08 (1H, d, J=6.5 Hz), 8.55 (1H, d, J=6.5 Hz), 9.35(1H, s);

[1759] MASS (ES+): m/e 295.

EXAMPLE 34

[1760] Compound E34 was obtained from Compound (103) according to amanner similar to Example 1 (240 mg).

[1761]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.22 (3H, s), 3.40 (3H, s), 4.08(2H, s), 6.44 (1H, d, J=15.8 Hz), 7.32 (2×1H, d, J=8 Hz), 7.42 (1H, d,J=15.8 Hz), 7.51 (2×1H, d, J=8 Hz);

[1762] MASS (ES+): m/e 356.

EXAMPLE 35

[1763] Compound E35 was obtained from Compound (105) according to amanner similar to Example 1 (160 mg).

[1764]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.42 (2H, s), 6.47 (1H, d, J=16 Hz),7.44 (1H, d, J=16 Hz), 7.44 (2×1H, d, J=8 Hz), 7.56 (2×1H, d, J=8 Hz),7.80 (1H, d, J=9 Hz), 8.19 (1H, dd, J=9, 2.2 Hz), 8.50 (1H, d, J=2.2Hz);

[1765] MASS (ES+): m/e 339.

EXAMPLE 36

[1766] Compound E36 was obtained from Compound (112) according to amanner similar to Example 1 (375 mg).

[1767]¹H-NMR (300 MHz, CDCl₃, δ): 5.66 (2H, s), 6.38 (1H, d, J=115.7Hz), 7.19 (2×1H, d, J=8.8 Hz), 7.43 (1H, d, J=15.7 Hz), 7.48-7.56 (2H,m), 7.58 (2×1H, d, J=8.8 Hz), 7.76-7.84 (2H, m), 10.75 (1H, br-s);

[1768] MASS (ES+): m/e 310.

EXAMPLE 37

[1769] Compound E37 was obtained from Compound (115) according to amanner similar to Example 1 (40 mg).

[1770]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.40-1.94 (8H, m), 3.85 (1H, m),4.54 (2H, s), 6.51 (1H, d, J=15.8 Hz), 7.28-7.80 (8H, m);

[1771] MASS (ES+): m/e 377.

EXAMPLE 38

[1772] Compound E38 was obtained from Compound (122) according to amanner similar to Example 1 (1.19 g).

[1773]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.67 (2H, s), 6.53 (1H, d, J=16 Hz),7.14 (1H, m), 7.27 (1H, m), 7.35 (1H, s), 7.41 (1H, dd, J=8, 8 Hz), 7.46(1H, d, J=16 Hz), 7.47-7.79 (2H, m), 7.77-7.87 (2H, m), 10.90 (1H, br);

[1774] MASS (ES+): m/e 310.

EXAMPLE 39

[1775] Compound E39 was obtained from Compound (125) according to amanner similar to Example 1 (110 mg).

[1776]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.05 (2×3H, t, J=7 Hz), 3.52 (4H,m), 4.51 (2H, s), 6.49 (1H, d, J=15.8 Hz), 7.41-7.53 (5H, m), 7.56-7.64(3H, m);

[1777] MASS (ES+): m/e 365.

EXAMPLE 40

[1778] Compound E40 was obtained from Compound (132) according to amanner similar to Example 1 (1472 mg).

[1779]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.84 (3H, s), 5.62 (2H, s), 6.43(1H, d, J=15.8 Hz), 7.14 (1H, d, J=8 Hz), 7.21 (1H, d, J=8 Hz), 7.28(1H, s), 7.42 (1H, d, J=15.8 Hz), 7.50-7.58 (2H, m), 7.78-7.86 (2H, m);

[1780] MASS (ES+): m/e 340.

EXAMPLE 41

[1781] Compound E41 was obtained from Compound (134) according tomanners similar to Preparation 9 and Example 1 (115 mg).

[1782]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.02 (2×3H, s), 4.52 (2H, s), 6.50(1H, d, J=16 Hz), 6.90-7.70 (8H, m);

[1783] MASS (ES+) m/e 337.

EXAMPLE 42

[1784] Compound E42 was obtained from Compound (141) according to amanner similar to Example 1 (450 mg).

[1785]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.82 (3H, s), 5.61 (2H, s), 6.40(1H, d, J=15.8 Hz), 7.11 (1H, d, J=8.8 Hz), 7.28 (1H, dd, J=8.8, 1.7Hz), 7.40 (1H, d, J=15.8 Hz), 7.43 (1H, d, J=1.7 Hz), 7.50-7.58 (2H, m),7.78-7.86 (2H, m);

[1786] MASS (ES+): m/e 340.

EXAMPLE 43

[1787] Compound E43 was obtained from Compound (144) according to amanner similar to Example 1 (160.8 mg).

[1788]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.45 (2H, s), 6.16 (2H, s), 6.47(1H, d, J=15.8 Hz), 7.43 (1H, d, J=8.1 Hz), 7.46 (1H, d, J=16.0 Hz),7.59 (2H, d, J=8.1 Hz);

[1789] MASS (ES+): m/e 338 (M+1)

EXAMPLE 44

[1790] Compound E44 was obtained from Compound (147) according to amanner similar to Example 1 (160.8 mg).

[1791]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.00 (3H, s), 4.42 (2H, s), 6.44(1H, d, J=16.2 Hz), 7.04 (1H, d, J=8.0 Hz), 7.27 (1H, d, J=8.4 Hz), 7.41(1H, t, J=8.2 Hz), 7.42 (2H, d, J=8.0 Hz), 7.45 (1H, d, J=16.0 Hz), 7.57(2H, d, J=8.0 Hz);

[1792] MASS (ES+): m/e 324 (M+1).

EXAMPLE 45

[1793] Compound E45 was obtained from Compound (151) according to amanner similar to Example 1 (481.2 mg).

[1794]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.87 (3H, d, J=7.4 Hz), 4.85 (1H, q,J=7.4 Hz), 6.49 (1H, d, J=16.1 Hz), 7.43 (1H, d, J=15.7 Hz), 7.49-7.52(2H, m), 7.51 (2H, d, J=8.5 Hz), 7.58 (2H, d, J=8.5 Hz), 7.74-7.77 (2H,m);

[1795] MASS (ES+): m/e 308 (M+1)

EXAMPLE 46

[1796] Compound E46 was obtained from Compound (155) according to amanner similar to Example 1 (576.3 mg).

[1797]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.88 (3H, d, J=7.3 Hz), 4.83 (1H, q,J=7.4 Hz), 6.50 (1H, d, J=15.7 Hz), 7.43 (1H, d, J=15.4 Hz), 7.48-7.51(2H, m), 7.53 (2H, d, J=8.2 Hz), 7.58 (2H, d, J=8.4 Hz), 7.74-7.77 (2H,m);

[1798] MASS (ES+): m/e 308 (M+1).

EXAMPLE 47

[1799] Compound E47 was obtained from Compound (158) according to amanner similar to Example 1 (274.9 mg).

[1800]¹H-NMR (300 MHz, DMSO-d₆, δ) 1.36 (3H, t, J=7.0 Hz), 4.08 (2H, q,J=7.0 Hz), 4.58 (2H, s), 6.49 (1H, d, J=15.7 Hz), 7.05 (2H, d, J=8.8Hz), 7.46 (1H, d, J=17.0 Hz), 7.50 (2H, d, J=8.4 Hz), 7.61 (2H, d, J=8.4Hz), 7.66 (2H, d, J=8.8 Hz), 7.77 (1H, dd, J=8.8, 1.5 Hz), 7.81 (1H, d,J=8.4 Hz), 7.90 (1H, s);

[1801] MASS (ES+): m/e 414 (M+1).

EXAMPLE 48

[1802] Compound E48 was obtained from Compound (161) according to amanner similar to Example 1 (231.1 mg).

[1803]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.60 (2H, s), 6.49 (1H, d, J=15.8Hz), 7.46 (1H, d, J=16.1 Hz), 7.52 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4Hz), 7.93 (2H, s), 8.19 (1H, s), 8.66 (1H, d, J=9.0 Hz), 8.81. (1H, dd,J=5.5, 1.5 Hz), 9.21 (1H, d, J=1.8 Hz);

[1804] MASS (ES+): m/e 371 (M+1).

EXAMPLE 49

[1805] Compound E49 was obtained from Compound (164) according to amanner similar to Example 1 (130.9 mg).

[1806]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.54 (2H, s), 6.48 (1H, d, J=15.8Hz), 7.46 (1H, d, J=15.8 Hz), 7.47 (2H, d, J=8.1 Hz), 7.58 (2H, t, J=7.0Hz), 7.60 (2H, d, J=8.1 Hz), 7.71 (1H, t, J=7.7 Hz), 7.76 (2H, d, J=7.4Hz), 7.83 (1H, dd, J=8.8, 1.5 Hz), 7.87 (2H, d, J=8.4 Hz), 8.01 (1H, s);

[1807] MASS (ES+): m/e 398 (M+1).

EXAMPLE 50

[1808] Compound E50 was obtained from Compound (166) according to amanner similar to Example 1 (69.3 mg).

[1809]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.51 (2H, s), 5.89 (1H, s), 6.46(1H, d, J=45.8 Hz), 7.20 (1H, t, J=7.0 Hz), 7.30 (2H, t, J=7.3 Hz), 7.39(2H, d, J=7.3 Hz), 7.46 (4H, m), 7.59 (2H, d, J=8.4 Hz), 7.65 (1H, d,J=8.4 Hz), 7.74 (1H, s);

[1810] MASS (ES+): m/e 398 (M+1).

EXAMPLE 51

[1811] Compound E51 was obtained from Compound (169) according to amanner similar to Example 1 (103.9 mg).

[1812]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.00 (6H, s), 4.57 (2H, s), 6.48(1H, d, J=15.8 Hz), 7.47 (1H, d, J=15.0 Hz), 7.50 (1H, d, J=8.1 Hz),7.61 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=9.1 Hz), 7.79 (2H, s), 7.87 (1H,s);

[1813] MASS (ES+): m/e 413 (M+1)

EXAMPLE 52

[1814] Compound E52 was obtained from Compound (172) according to amanner similar to Example 1 (203.9 mg).

[1815]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.46 (2H, s), 6.46 (1H, d, J=16.1Hz), 7.44 (2H, d, J=8.5 Hz), 7.45 (1H, d, J=16.0 Hz), 7.57 (2H, d, J=8.5Hz), 7.69 (1H, d, J=8.5 Hz), 7.85 (1H, d, J=7.8 Hz), 8.03 (1H, s);

[1816] MASS (ES+): m/e 361 (M+1).

EXAMPLE 53

[1817] Compound E53 was obtained from Compound (175) according to amanner similar to Example 1 (419.6 mg).

[1818]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.35 (2H, s), 6.46 (1H, d, J=15.7Hz), 7.31-7.40 (2H, m), 7.42 (2H, d, J=8.0 Hz), 7.43 (1H, d, J=16.0 Hz),7.56 (2H, d, J=8.0 Hz);

[1819] MASS (ES+): m/e 330 (M+1).

EXAMPLE 54

[1820] Compound E54 was obtained from Compound (178) according to amanner similar to Example 1 (90.7 mg).

[1821]¹H-NMR (300 MHz, DMSO-d₆, δ): 0.94 (6H, d, J=6.6 Hz), 1.64 (2H,dt, J=6.6, 6.6 Hz), 1.80 (1H, hept, J=6.6 Hz), 4.07 (2H, t, J=6.6 Hz),4.51 (2H, s), 6.48 (1H, d, J=16.2 Hz), 7.11 (1H, dd, J=2.1,9.0 Hz), 7.21(1H, d, J=2.1 Hz), 7.44 (2H, d, J=8.4 Hz), 7.45 (1H, d, J=16.2 Hz), 7.59(2H, d, J=8.5 Hz), 7.63 (1H, d, J=9.0 Hz);

[1822] MASS (ES+): m/e 380 (M+1).

EXAMPLE 55

[1823] Compound E55 was obtained from Compound (181) according to amanner similar to Example 1 (215.8 mg).

[1824]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.29 (6H, d, J=6.1 Hz), 4.51 (2H,s), 4.70 (1H, hept, J=6.1 Hz), 6.48 (1H, d, J=16.0 Hz), 7.09 (1H, dd,J=2.2, 8.9 Hz), 7.20 (1H, d, J=2.2 Hz), 7.45 (1H, d, J=16.0 Hz), 7.47(2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.1 Hz), 7.63 (1H, d, J=8.9 Hz);

[1825] MASS (ES+): m/e 352 (M+1)

EXAMPLE 56

[1826] Compound E56 was obtained from Compound (184) according to amanner similar to Example 1 (387.8 mg).

[1827]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.52 (2H, s), 6.48 (1H, d, J=16.1Hz), 7.04 (2H, d, J=7.7 Hz), 7.18 (1H, t, J=7.7 Hz), 7.22 (1H, dd,J=8.8, 2.2 Hz), 7.30 (1H, d, J=2.2 Hz), 7.41 (2H, t, J=8.0 Hz), 7.46(1H, d, J=16.0 Hz), 7.47 (2H, d, J=8.1 Hz), 7.57 (2H, d, J=7.7 Hz), 7.77(1H, d, J=9.2 Hz);

[1828] MASS (ES+): m/e 386 (M+1)

EXAMPLE 57

[1829] Compound E57 was obtained from Compound (187) according to amanner similar to Example 1 (78.2 mg).

[1830]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.85 (3H, s), 4.52 (2H, s), 6.48(1H, d, J=15.7 Hz), 7.12 (1H, dd, J=8.8, 2.2 Hz), 7.20 (1H, d, J=2.2Hz), 7.45 (1H, d, J=15.0 Hz), 7.46 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4Hz), 7.65 (1H, d, J=9.2 Hz);

[1831] MASS (ES+): m/e 324 (M+1).

EXAMPLE 58

[1832] To a solution of Compound (277) (2.46 g) in MeOH (12 mL) wasadded hydrogen chloride methanol reagent 10 (15 mL, Tokyo Kasei KogyoCo., Ltd.), and the mixture was stirred at ambient temperature for 2hrs. The reaction mixture was diluted with isopropyl ether (50 mL) andthe precipitate was collected by filtration. The obtained pale yellowpowder was crystallized with a mixed solvent (EtOH: H₂O=6: 4, 100 mL) togive Compound E58 (1.23 g) as colorless powder.

[1833]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.39 (2H, s), 6.46 (1H, d, J=15.7Hz), 7.43 (3H, m), 7.50 (1H, t, J=6.6 Hz), 7.52 (2H, t, J=7.0 Hz), 7.58(2H, d, J=8.0 Hz), 7.82 (2H, d, J=7.4 Hz), 8.06 (1H, s);

[1834] MASS (ES+): m/e 320 (M+1).

EXAMPLE 59

[1835] Compound E59 was obtained from Compound (278) according to amanner similar to Example 58 (274 mg).

[1836]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.81 (3H, s), 4.33 (2H, s), 6.49(1H, d, J=16.1 Hz), 7.36-7.65 (8H, m), 7.74-7.85 (2H, m);

[1837] MASS (ES+): m/z 378 (M+1, free).

EXAMPLE 60

[1838] Compound E60 was obtained from Compound (188) according to amanner similar to Example 58 (1.36 g).

[1839]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.80 (3H, s), 4.26 (2H, s), 6.45(1H, d, J=15.8 Hz), 7.38-7.48 (3H, m), 7.52-7.61 (4H, m), 7.82 (2H, d);

[1840] MASS (ES+): m/z 412 (M+1, free).

EXAMPLE 61

[1841] Compound E61 was obtained from Compound (193) according to amanner similar to Example 58 (68 mg).

[1842]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.32 (2H, s), 6.47 (1H, d, J=16.1Hz), 7.39-7.61 (6H, m), 7.62-7.89 (4H, m);

[1843] MASS (ES+): m/z 363 (M+1, free).

EXAMPLE 62

[1844] Compound E61 was obtained from Compound (194) according to amanner similar to Example 58 (40 mg).

[1845]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.10 (2H, s), 6.44 (1H, d, J=15.8Hz), 7.31-7.64 (8H, m), 7.76-7.86 (2H, m);

[1846] MASS (ES+): m/z 345 (M+1, free).

EXAMPLE 63

[1847] Compound E63 was obtained from Compound (203) according to amanner similar to Example 58 (212 mg).

[1848]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.40 (2H, s), 6.47 (1H, d, J=16 Hz),7.34-7.50 (5H, m), 7.58 (2×1H, d, J=8 Hz), 7.87-7.96 (2H, m), 8.05 (1H,s), 10.81 (1H, s);

[1849] MASS (ES+): m/z 338.

EXAMPLE 64

[1850] Compound E64 was obtained from Compound (189) according to amanner similar to Example 58 (81 mg).

[1851]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.40 (2H, s), 6.47 (1H, d, J=15.2Hz), 7.44 (1H, d, J=15.2 Hz), 7.45 (2H, d, J=8.4 Hz), 7.55-7.66 (4H, m,J=8.4 Hz), 7.89 (2H, d, J=8.8 Hz), 8.11 (1H, s);

[1852] MASS (ES+): m/z 354 (M+1, free).

EXAMPLE 65

[1853] Compound E65 was obtained from Compound (209) according to amanner similar to Example 58 (145 mg).

[1854]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.52 (3H, s), 2.53 (3H, s), 4.27(2H, s), 6.47 (1H, d, J=16 Hz), 7.41 (2×1H, d, J=8 Hz), 7.44 (1H, d,J=16 Hz), 7.56 (2×1H, d, J=8 Hz), 10.82 (1H, br-s);

[1855] MASS: not detected.

EXAMPLE 66

[1856] Compound E66 was obtained from Compound (208) according to amanner similar to Example 58 (364 mg).

[1857]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.25 (3H, s), 4.29 (2H, s), 6.48(1H, d, J=16 Hz), 7.39-7.50 (3H, m), 7.53-7.63 (4H, m), 7.71 (1H, m),7.87 (2×1H, d, J=7.5 Hz), 10.81 (1H, br-s); MASS (ES+): m/z 362.

EXAMPLE 67

[1858] Compound E67 was obtained from Compound (222) according to amanner similar to Example 58 (90 mg).

[1859]¹H-NMR (300 MHz, DMSO-d₆, δ): 6.52 (1H, d, J=16.1 Hz), 7.40-7.57(6H, m), 7.63 (2H, d, J=8.1 Hz), 7.86 (2H, d, J=7.0 Hz), 8.29 (1H, s),9.47 (1H, s);

[1860] MASS (ES+): m/z 320 (M+1, free).

EXAMPLE 68

[1861] Compound E68 was obtained from Compound (190) according to amanner similar to Example 58 (80 mg).

[1862]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.43 (2H, s), 6.49 (1H, d, J=16.1Hz), 7.38-7.57 (7H, m), 7.64 (1H, s), 7.87 (2H, d, J=7.0 Hz), 8.09 (1H,s);

[1863] MASS (ES+): m/z 320 (M+1, free).

EXAMPLE 69

[1864] Compound E69 was obtained from Compound (191) according to amanner similar to Example 58 (47 mg).

[1865]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.09 (2H, s), 6.47 (1H, d, J=16.1Hz), 7.29-7.59 (8H, m), 7.70-7.77 (2H, m);

[1866] MASS (ES+): m/z 354 (M+1, free).

EXAMPLE 70

[1867] Compound E70 was obtained from Compound (279) according to amanner similar to Example 58 (1.34 mg).

[1868]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.81-(3H, s), 4.38 (2H, s), 6.47(1H, d, J=16.1 Hz), 7.08 (2H, d, J=8.8 Hz), 7.44 (2H, d, J=8.4 Hz), 7.45(1H, d, J=15.1 Hz), 7.58 (2H, d, J=8.4 Hz), 7.77 (2H, d, J=8.8 Hz), 7.94(1H, s);

[1869] MASS (ES+): m/e 350 (M+1).

EXAMPLE 71

[1870] Compound E71 was obtained from Compound (280) according to amanner similar to Example 58 (482 mg).

[1871]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.83 (3H, s), 4.40 (2H, s), 6.47(1H, d, J=15.8 Hz), 7.00 (1H, m), 7.39-7.47 (6H, m), 7.58 (2H, d, J=8.1Hz), 8.09 (1H, s);

[1872] MASS (ES+): m/e 350 (M+1).

EXAMPLE 72

[1873] Compound E72 was obtained from Compound (281) according to amanner similar to Example 58 (498 mg).

[1874]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.93 (3H, s), 4.40 (2H, s), 6.46(1H, d, J=15.7 Hz), 7.11 (1H, t, J=8.1 Hz), 7.21 (1H, d, J=8.1 Hz), 7.43(2+1+1H, d, J=8.1 Hz), 7.58 (2H, d, J=8.1 Hz), 7.80 (1H, dd, J=8.1, 1.6Hz), 7.88 (1H, s);

[1875] MASS (ES+): m/z 350 (M+1).

EXAMPLE 73

[1876] Compound E73 was obtained from Compound (282) according to amanner similar to Example 58 (94.8 mg).

[1877]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.13 (2H, s), 6.44 (1H, d, J=15.8Hz), 7.37 (2H, d, J=8.4 Hz), 7.38 (2H, t, J=8.1 Hz), 7.43 (1H, d, J=15.4Hz), 7.50 (2H, t, J=8.1 Hz), 7.54 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.1Hz);

[1878] MASS (ES+): m/e 398 (M+1).

EXAMPLE 74

[1879] Compound E74 was obtained from Compound (283) according to amanner similar to Example 58 (76 mg).

[1880]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.03 (2H, s), 6.43 (1H, d, J=16.1Hz), 7.32 (1H, t, J=7.4 Hz), 7.34 (2H, d, J=7.4 Hz), 7.43 (1H, d, J=15.4Hz), 7.47 (2H, t, J=7.7 Hz), 7.52 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.1Hz);

[1881] MASS (ES+): m/e 354 (M+1).

EXAMPLE 75

[1882] Compound E75 was obtained from Compound (285) according to amanner similar to Example 58 (74.3 mg).

[1883]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.64 (2H, br.), 1.72 (4H, br.), 2.88(2H, br.), 3.27 (2H, br.), 4.35 (2H, s), 4.43 (2H, s), 6.47 (1H, d,J=15.7 Hz), 7.45 (1H, d, J=15.7 Hz), 7.49 (2+1H, m), 7.56 (2+2H, m).,7.67 (2H, d, J=7.4 Hz);

[1884] MASS (ES+): m/e 417 (M+1).

EXAMPLE 76

[1885] Compound E76 was obtained from Compound (286) according to amanner similar to Example 58 (76.8 mg).

[1886]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.15 (4H, br.), 3.81 (4H, br.), 4.36(2H, s), 4.46 (2H, s), 6.48 (1H, d, J=15.8 Hz), 7.45 (1H, d, J=16.1 Hz),7.49 (2+1H, m), 7.55 (2+2H, m), 7.71 (2H, d, J=7.3 Hz);

[1887] MASS (ES+): m/e 419 (M+1).

EXAMPLE 77

[1888] Compound E77 was obtained from Compound (287) according to amanner similar to Example 58 (76 mg).

[1889]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.79 (3H, s), 4.05 (2H, s), 6.44(1H, d, J=15.8 Hz), 7.05 (2H, d, J=8.1 Hz), 7.34 (2H, d, J=8.4 Hz), 7.43(1H, d, J=16.1 Hz), 7.52 (2H, d, J=8.1 Hz), 7.64 (2H, d, J=8.1 Hz);

[1890] MASS (ES+): m/e 384 (M+1).

EXAMPLE 78

[1891] Compound E78 was obtained from Compound (223) according to amanner similar to Example 58 (280 mg).

[1892]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.69 (3H, s), 5.43 (2H, s), 6.49(1H, d, J=15.8 Hz), 7.44 (3H, m), 7.47 (1H, d, J=15.8 Hz), 7.53 (2H, t,J=7.3 Hz), 7.62 (2H, d, J=8.4 Hz), 7.81 (2H, d, J=7.0 Hz), 8.16 (1H, s)

[1893] MASS (ES+): m/e 334 (M+1).

EXAMPLE 79

[1894] Compound E79 was obtained from Compound (224) according to amanner similar to Example 58 (432.4 mg).

[1895]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.31 (3H, s), 5.53 (2H, s), 6.50(1H, d, J=15.8 Hz), 7.40 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=15.8 Hz),7.63 (2H, d, J=8.1 Hz), 7.64 (4H, s), 9.36 (1H, s);

[1896] MASS (ES+): m/z 368 (M+1).

EXAMPLE 80

[1897] Compound E80 was obtained from Compound (288) according to amanner similar to Example 58 (176 mg).

[1898]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.47 (2H, s), 6.52 (1H, d, J=15.8Hz), 7.41-7.53 (6H, m), 7.60 (1H, d, J=6.2 Hz), 7.68 (1H, s), 7.84 (2H,d, J=7.0 Hz), 8.26 (1H, s), 9.34 (1H, s);

[1899] MASS (ES+): m/e 319 (M+1).

EXAMPLE 81

[1900] Compound E81 was obtained from Compound (289) according to amanner similar to Example 58 (268 mg).

[1901]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.33 (3H, s), 5.54 (2H, s), 6.53(1H, d, J=16.1 Hz), 7.369-7.54 (4H, m), 7.58 (1H, s), 7.63 (2H, d, J=8.4Hz), 7.68 (2H, d, J=8.4 Hz), 9.42 (1H, s);

[1902] MASS (ES+): m/e 368 (M+1).

EXAMPLE 82

[1903] Compound E82 was obtained from Compound (321) according to amanner similar to Example 58 (220 mg).

[1904]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.50 (2H, s), 6.48 (1H, d, J=16.1Hz), 7.15 (2H, d, J=8.1 Hz), 7.41 (1H, d, J=16.1 Hz), 7.53 (2H, d, J=8.1Hz), 7.59-7.78 (−5H, m), 7.88-7.97 (2H, m);

[1905] MASS (ES+): m/z 320 (M+1, free).

EXAMPLE 83

[1906] Compound E83 was obtained from Compound (323) according to amanner similar to Example 58 (60 mg).

[1907]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.73 (3H, d, J=4.8 Hz), 4.28 (2H,s), 6.46 (1H, d, J=15.8 Hz), 7.35-7.61 (7H, m), 7.70-7.80 (2H, m),8.24-8.37 (1H, m);

[1908] MASS (ES+): m/z 377 (M+1, free).

EXAMPLE 84

[1909] Compound E84 was obtained from Compound (290) according to amanner similar to Example 58 (22.2 mg).

[1910]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.78 (3H, s), 4.22 (2H, s), 6.44(1H, d, J=15.8 Hz), 7.39 (2H, d, J=8.1 Hz), 7.43 (1H, d, J=15.8 Hz),7.48 (3H, m), 7.54 (2H, d, J=8.4 Hz), 7.76 (2H, m);

[1911] MASS (ES+): m/e 378 (M+1).

EXAMPLE 85

[1912] Compound E85 was obtained from Compound (291) according to amanner similar to Example 58 (13.5 mg).

[1913]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.29 (9H, s), 4.32 (2H, s), 6.46(1H, d, J=15.8 Hz), 7.29 (1H, s), 7.39 (2H, d, J=8.4 Hz), 7.44 (1H, d,J=16.1 Hz), 7.57 (2H, d, J=8.1 Hz);

[1914] MASS (ES+): m/z 300 (M+1).

EXAMPLE 86

[1915] Compound E86 was obtained from Compound (198) according to amanner similar to Example 58 (491 mg).

[1916]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.23 (3H, t, J=7.0 Hz), 4.24 (2H,s), 4.26 (2H, q, J=7.0 Hz), 6.44 (1H, d, J=15.8 Hz), 7.41 (2H, d, J=8.0Hz), 7.43 (1H, d, J=15.4 Hz), 7.48 (3H, m), 7.55 (2H, d, J=8.1 Hz), 7.75(2H, m);

[1917] MASS (ES+): m/e 392 (M+1).

EXAMPLE 87

[1918] Compound E87 was obtained from Compound (332) according to amanner similar to Example 58 (86.7 mg).

[1919]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.71 (3H, s), 2.98 (3H, s), 4.32(2H, s), 6.46 (1H, d, J=16.1 Hz), 7.41-7.60 (10H, m);

[1920] MASS: Not Detected.

EXAMPLE 88

[1921] Compound E88 was obtained from Compound (325) according to amanner similar to Example 58 (35.8 mg).

[1922]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.09 (2H, br.), 1.49 (4H, br.), 3.12(4H, br.), 4.34 (2H, s), 6.47 (1H, d, J=15.8 Hz), 7.42-7.60 (10H, m);

[1923] MASS (ES+): m/e 431 (M+1).

EXAMPLE 89

[1924] Compound E89 was obtained from Compound (326) according to amanner similar to Example 58 (40.5 mg).

[1925]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.11 (6H, d, J=6.6 Hz), 4.02 (1H,m), 4.23 (2H, s), 6.44 (1H, d, J=15.8 Hz), 7.40 (2H, d, J=7.7 Hz), 7.48(4H, m), 7.56 (2H, d, J=8.1 Hz), 7.73 (2H, d, J=8.1 Hz);

[1926] MASS (ES+): m/e 405 (M+1).

EXAMPLE 90

[1927] Compound E90 was obtained from Compound (284) according to amanner similar to Example 58 (11.1 mg).

[1928]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.71 (6H, s), 4.21 (2H, s), 4.38(2H, s), 6.44 (1H, d, J=16.1 Hz), 7.40 (3H, m), 7.48 (2H, m), 7.55 (5H,m);

[1929] MASS (ES+): m/e 377 (M+1).

EXAMPLE 91

[1930] Compound E91 was obtained from Compound (323) according to amanner similar to Example 58 (40.1 mg).

[1931]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.27 (2H, s), 6.45 (1H, d, J=15.8Hz), 7.41-7.58 (8H, m), 7.78 (2H, m);

[1932] MASS: Not Detected.

EXAMPLE 92

[1933] Compound E92 was obtained from Compound (327) according to amanner similar to Example 58 (14.8 mg).

[1934]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.37 (2H, s), 4.60 (2H, s), 6.47(1H, d, J=15.0 Hz), 7.42-7.60 (8H, m), 7.67 (2H, d, J=7.0 Hz);

[1935] MASS (ES+): m/e 350 (M+1).

EXAMPLE 93

[1936] Compound E93 was obtained from Compound (329) according to amanner similar to Example 58 (145 mg).

[1937]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.34 (3H, s), 4.37 (2H, s), 4.51(2H, s), 6.46 (1H, d, J=15.8 Hz), 7.43-7.65 (10H, m);

[1938] MASS (ES+): m/e 364 (M+1).

EXAMPLE 94

[1939] Compound E94 was obtained from Compound (330) according to amanner similar to Example 58 (42.4 mg).

[1940]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.17 (3H, s), 4.41 (2H, s), 6.46(1H, d, J=16.1 Hz), 7.37-7.44 (2H, m), 7.45 (1H, d, J=15.8 Hz),7.52-7.60 (6H, m), 7.71 (1H, m);

[1941] MASS (ES+): m/z 362 (M+1).

EXAMPLE 95

[1942] Compound E95 was obtained from Compound (225) according to amanner similar to Example 58 (176 mg).

[1943]¹H-NMR (300 MHz, DMSO-d₆, δ): 5.47 (2H, s), 6.53 (1H, d, J=16 Hz),7.44 (1H, d, J=16 Hz), 7.45 (2×1H, d, J=8.5 Hz), 7.60 (2×1H, d, J=8.5Hz), 7.72 (1H, dd, J=1.7, 1.5 Hz), 7.81 (1H, dd, J=1.7, 1.3 Hz), 9.34(1H, dd, J=1.5, 1.3 Hz), 10.89 (1H, br-s), 14.73 (1H, br-s);

[1944] MASS (ES+): m/e 244.

EXAMPLE 96

[1945] Compound E96 was obtained from Compound (210) according to amanner similar to Example 58 (21 mg).

[1946]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.96-2.03 (4H, m), 3.24-3.31 (4H,m), 4.49 (2H, s), 6.49 (1H, d, J=16 Hz), 6.60 (1H, s), 6.83 (1H, dd,J=2, 8 Hz), 7.42-7.62 (6H, m);

[1947] MASS (ES+): m/z 363 (M+1).

EXAMPLE 97

[1948] Compound E97 was obtained from Compound (328) according to amanner similar to Example 58 (7.9 mg).

[1949]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.55 (2H, s), 4.66 (2H, s), 6.48(1H, d, J=16 Hz), 7.43-7.51 (4H, m), 7.60 (2H, d, J=8 Hz), 7.71 (2H, d,J=8 Hz);

[1950] MASS (ES+): m/z 324 (M+1).

EXAMPLE 98

[1951] Compound E98 was obtained from Compound (333) according to amanner similar to Example 58 (72 mg).

[1952]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.77-1.92 (4H, m), 3.33-3.54 (4H,m), 4.57 (2H, s), 6.50 (1H, d, J=16 Hz), 7.45 (1H, d, J=16 Hz), 7.50(2H, d, J=8 Hz), 7.60 (2H, d, J=8 Hz), 7.64 (1H, dd, J=2, 8 Hz), 7.80(1H, d, J=8 Hz), 7.88 (1H, s);

[1953] MASS (ES+): m/z 391 (M+1)

EXAMPLE 99

[1954] Compound E99 was obtained from Compound (334) according to amanner similar to Example 58 (12 mg).

[1955]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.24 (6H, t, J=7 Hz), 2.93-3.09 (4H,m), 4.25 (2H, s), 4.32-4.39 (2H, m), 6.78 (1H, d, J=16 Hz), 7.38-7.65(7H, m), 7.82 (1H, s);

[1956] MASS (ES+): m/z 379 (M+1).

EXAMPLE 100

[1957] Compound E100 was obtained from Compound (316) according to amanner similar to Example 58 (40 mg).

[1958]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.71 (3H, s), 4.10 (2H, s), 5.11(2H, s), 6.41 (1H, d, J=16 Hz), 6.86 (2H, d, J=8 Hz), 7.09 (2H, d, J=8Hz), 7.16 (2H, d, J=8 Hz), 7.36-7.52 (3H, m), 7.80 (1H, s);

[1959] MASS (ES−): m/z 430 (M−1).

EXAMPLE 101

[1960] Compound E101 was obtained from Compound (317) according to amanner similar to Example 58 (164 mg).

[1961]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.65-1.79 (6H, m), 1.84-1.93 (6H,m), 2.00-2.07 (3H, m), 4.32 (2H, s), 6.47 (1H, d, J=16 Hz), 7.25 (1H,s), 7.38-7.48 (3H, m), 7.56 (2H, d, J=8 Hz);

[1962] MASS (ES+): m/z 378 (M+1).

EXAMPLE 102

[1963] Compound E102 was obtained from Compound (338) according to amanner similar to Example 58 (35 mg).

[1964]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.31 (3H, t, J=7 Hz), 4.28 (2H, s),4.33 (2H, q, J=7 Hz), 6.47 (1H, d, J=16 Hz), 7.37 (2H, d, J=8 Hz), 7.43(1H, d, J=16 Hz), 7.55 (2H, d, J=8 Hz), 8.23 (1H, s);

[1965] MASS (ES+): m/z 316 (M+1).

EXAMPLE 103

[1966] Compound E103 was obtained from Compound (312) according to amanner similar to Example 58 (138 mg).

[1967]¹H-NMR (300 MHz, DMSO-d, 6): 2.36 (2H, m), 3.30 (2H, t, J=7.4 Hz),4.15 (2H, t, J=5.8 Hz), 6.30 (1H, d, J=16.1 Hz), 6.79 (2H, d, J=8.8 Hz),7.38 (1H, d, J=15.8 Hz), 7.45 (2H, d, J=8.8 Hz), 7.54 (2H, m), 7.78 (2H,m);

[1968] MASS (ES+): m/e 338 (M+1).

EXAMPLE 104

[1969] Compound E104 was obtained from Compound (313) according to amanner similar to Example 58 (174 mg).

[1970]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.84 (2H, m), 2.03 (2H, m), 3.21(2H, t, J=7.4 Hz), 4.07 (2H, t, J=6.4 Hz), 6.31 (1H, d, J=15.4 Hz), 6.96(2H, d, J=8.8 Hz), 7.40 (1H, d, J=15.8 Hz), 7.49 (2H, d, J=8.1 Hz), 7.53(2H, m), 7.78 (2H, m);

[1971] MASS (ES+): m/e 352 (M+1).

EXAMPLE 105

[1972] Compound E105 was obtained from Compound (314) according to amanner similar to Example 58 (153 mg).

[1973]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.21 (2H, quint., J=7.3 Hz), 2.74(2H, t, J=7.3 Hz), 3.14 (2H, t, J=7.7 Hz), 6.42 (1H, d, J=16.1 Hz), 7.29(2H, d, J=8.0 Hz), 7.41 (1H, d, J=15.8 Hz), 7.48 (2H, d, J=7.7 Hz), 7.52(2H, m), 7.76 (2H, m);

[1974] MASS (ES+): m/e 322 (M+1).

EXAMPLE 106

[1975] A suspension of Compound E116 (1.23 g, described later in Example116) and benzenesulfonic acid (732 mg) in 80% aqueous ethanol (20 mL)was dissolved at 90° C. The insoluble materials were removed byfiltration and the filtrate was evaporated in vacuo to give a crudesolid. This solid was recrystallized from 80% aqueous ethanol to giveCompound E106 as a pale yellow crystal (820 mg).

[1976]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.53 (2H, s), 6.47 (1H, d, J=16 Hz),7.28-7.36 (3H, m), 7.41-7.56 (5H, m), 7.57-7.66 (4H, m), 7.72-7.81 (2H,m), 10.78 (1H, s);

[1977] MASS (ES+): m/z 294.

EXAMPLE 107

[1978] A suspension of Compound E116 (1.80 g, described later in Example116) and (1R)-(−)-10-camphorsulfonic acid (855 mg) in 80% aqueousethanol (20 mL) was dissolved at 90° C. The insoluble materials wereremoved by filtration, and the filtrate was evaporated in vacuo to givea crude solid. This solid was recrystallized from 80% aqueous ethanol togive Compound E107 as a white crystal (1.30 g).

[1979]¹H-NMR (300 MHz, DMSO-d₆, δ): 0.74 (3H, s), 1.05 (3H, s),1.20-1.35 (2H, m), 1.74-1.96 (3H, m), 2.24 (1H, m), 2.39 (1H, d, J=14.7Hz), 2.69 (1H, m), 2.89 (1H, d, J=14.7 Hz), 4.55 (2H, s), 6.48 (1H, d,J=15.7 Hz), 7.42-7.58 (5H, m), 7.61 (2×1H, d, J=8 Hz), 7.74-7.82 (2H,m), 10.79 (1H, s);

[1980] MASS (ES+): m/z 294.

EXAMPLE 108

[1981] To a stirred suspension of Compound E116 (1.0 g, described laterin Example 116) in ethanol (20 mL) was added 4-methylbenzenesulfonicacid monohydrate (713 mg) at ambient temperature. The resultingsuspension was stirred at 70° C. for 1 hr, during which time water (0.1mL) was added to the mixture in order to dissolve some insolublematerials. The mixture was allowed to cool to ambient temperature andthe stirring was continued for additional 1 hr. The precipitate wasfiltered, washed with ethanol (5 mL, 2 times) and dried to afford crudeCompound E108 (1.58 g) as a pale tan solid. The Compound E110 was usedwithout further purification.

EXAMPLE 109

[1982] A suspension of crude Compound E108 (salt, 710 mg) in 80% aqueousacetonitrile (20 mL) was heated at 90° C. for 15 min. The insolublematerials were removed by filtration and the resulting filtrate wasallowed to cool to ambient temperature. The solution was stirred atambient temperature for 1 hr and then in an ice bath for 0.5 hr. Theprecipitate formed was filtered, washed with acetonitrile (5 mL, 2times) and dried to afford Compound E111 (370 mg) as a pale tan solid.

[1983] m.p. 228.5-230.5° C.

[1984]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.29 (3H, s), 4.54 (2H, s), 6.47(1H, d, J=15.8 Hz), 7.11 (2H, d, J=7.7 Hz), 7.42-7.57 (7H, m), 7.61 (2H,d, J=8.4 Hz), 7.72-7.82 (2H, m);

[1985] MASS (ES+): m/z 294 (M+1, free).

EXAMPLE 110

[1986] To a solution of Compound (292) (42 mg) in MeOH (1 mL) was addedhydrogen chloride methanol reagent 10 (0.8 mL, manufactured by TokyoKasei Kogyo Co., Ltd.), and the mixture was stirred at ambienttemperature for 2 hrs. To the reaction mixture was added saturatedaqueous NaHCO₃ solution and extracted with AcOEt. The organic phase wassequentially washed with saturated aqueous NaHCO₃ solution, water andbrine, and the solvent was removed in vacuo. The obtained colorlesssolid was triturated with MeCN to give Compound E110 (4.8 mg) ascolorless powder.

[1987]¹H-NMR (300 MHz, DMSO-d₆, δ): 1.28 (4H, m), 1.69 (4H, m), 1.90(2H, m), 2.37 (1H, m), 3.91 (2H, s), 6.41 (1H, d, J=15.8 Hz), 6.62 (1H,s), 7.26 (2H, d, J=8.1 Hz), 7.41 (1H, d, J=15.8 Hz), 7.47 (2H, d, J=7.7Hz);

[1988] MASS (ES+): m/z 326 (M+1)

EXAMPLE 111

[1989] Compound E111 was obtained from Compound (284) according to amanner similar to Example 110 (289 mg).

[1990]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.16 (6H, s), 3.44 (2H, s), 4.00(2H, s), 6.41 (1H, d, J=16.5 Hz), 7.18 (1H, t, J=7.0 Hz), 7.32 (2H, d,J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.41 (1H, d, J=15.8 Hz), 7.50 (2H, d,J=7.7 Hz), 7.70 (2H, d, J=7.3 Hz);

[1991] MASS (ES+): m/z 377 (M+1).

EXAMPLE 112

[1992] Compound E112 was obtained from Compound (197) according to amanner similar to Example 58 (22.5 mg).

[1993] m.p. 235-239° C.

[1994]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.34 (2H, s), 6.47 (1H, d, J=15.8Hz), 7.37 (2H, d, J=8.1 Hz), 7.44 (1H, d, J=15.8 Hz), 7.57 (2H, d, J=8.1Hz), 7.60 (2H, s);

[1995] MASS (ES+) m/z 243 (M+1, free).

EXAMPLE 113

[1996] To a stirred solution of[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid(832 mg, described later in Example 116) in ethanol (10 mL) was addedCompound E116 (1.0 g, described later in Example 118) at ambienttemperature. The resulting suspension was heated at 60° C. for 1 hr andthen allowed to cool to ambient temperature. The suspension was furtherstirred at ambient temperature for 1 hr. The precipitate was filtered,washed with ethanol (2 mL, 3 times) and dried to afford Compound E113(1.73 g) as a pale tan solid. The Compound E113 was used in thefollowing Example 114 without further purification.

EXAMPLE 114

[1997] A suspension of crude Compound E113 (salt, 700 mg) in 90% aqueousacetonitrile (20 mL) was heated at 90° C. for 5 min. The insolublematerials were removed by filtration and the resulting filtrate washeated at 90° C. again. The solution was allowed to cool to ambienttemperature and stirred at the same temperature for 1 hr. Theprecipitate was filtered, washed with acetonitrile (2 mL, 2 times) anddried to afford Compound E114 (522 mg) as a pale tan solid.

[1998] m.p. 185.5-194.5° C.

[1999]¹H-NMR (300 MHz, DMSO-d₆, δ): 0.74 (3H, s), 1.05 (3H, s),1.20-1.35 (2H, m), 1.79 (1H, d, J=18.0 Hz), 1.80-1.90 (1H, m), 1.93 (1H,t, J=4.2 Hz), 2.23 (1H, dt, J=18.0, 4.2 Hz), 2.39 (1H, d, J=14.7 Hz),2.61-2.76 (1H, m), 2.89 (1H, d, J=14.7 Hz), 4.54 (2H, s), 6.48 (1H, d,J=16.1 Hz), 7.41-7.57 (5H, m), 7.61 (2H, d, J=8.1 Hz), 7.73-7.82 (2H,m), 10.79 (1H, br.s);

[2000] MASS (ES+): m/z 294 (M+1, free).

EXAMPLE 115

[2001] To a mixture of Compound (322) (as a mixture of two regioisomers,310 mg in total) in methanol (1 mL) was added 10% hydrogen chloride inmethanol (3 mL) at ambient temperature for 20 min. The mixture wasconcentrated in vacuo, and the residue was purified by preparative highperformance liquid chromatography (column; Mightysil RP-18 GP 250-20Kanto Chemical Co., Inc.) eluting with a gradient solvent system fromacetonitrile in water (10:90 v/v) to acetonitrile in water (50:50 v/v).The residue was lyophilized to give a mixture of Compound E115 as amixture of two regioisomers (85 mg in total) as a pale red viscous oil.

[2002]¹H-NMR (300 MHz, DMSO-d₆, δ): (for a mixture of two regioisomers)2.17 (1.2H, s), 2.25 (1.8H, s), 5.39 (1.2H, s), 5.47 (0.8H, s), 6.52(1H, d, J=15.8 Hz), 7.18-7.37 (1.2H, m), 7.39-7.54 (2.8H, m), 7.60(1.2H, d, J=8.1 Hz), 7.75 (0.8H, d, J=8.1 Hz), 9.20 (0.6H, s), 9.25(0.4H, s);

[2003] MASS (ES+): (for a mixture of two regioisomers) m/z 258 (M+1).

EXAMPLE 116

[2004] To a suspension of Compound E1 (990 mg) in ethanol (10 mL) wasadded 1N sodium hydroxide solution (3.0 mL), and the mixture was stirredat 70° C. for 2 hrs. The resulting precipitate was collected byfiltration and washed with ethanol and H₂O to give Compound E116 (810mg) as a white powder.

[2005]¹H-NMR (300 MHz, DMSO-d, 6): 4.19 (2H, s), 6.41 (1H, d, J=16 Hz),7.07-7.16 (2H, m), 7.33-7.55 (7H, m).

EXAMPLE 117

[2006] To a suspension of Compound E116 (147 mg) in ethanol (5 mL) wasadded 1N sodium hydroxide solution (0.501 mL), and the mixture wasstirred at room temperature for 1 hour. The resulting mixture wasevaporated in vacuo and triturated with isopropyl ether to give CompoundE117 (162 mg) as a pale green powder.

[2007]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.13 (2H, s), 6.32 (1H, d, J=16 Hz),6.89 (1H, d, J=16 Hz), 7.07-7.14 (2H, m), 7.24 (2H, d, J=8 Hz), 7.36(2H, d, J=8 Hz), 7.43-7.50 (2H, m).

EXAMPLE 118

[2008] To a suspension of Compound E116 (147 mg) in ethanol (5 mL) wasadded 1N methanesulfonic acid solution (0.501 mL), and the mixture wasstirred at room temperature for 2 hrs. The resulting precipitate wascollected by filtration and washed with ethanol to give Compound E118(91 mg) as a white powder.

[2009]¹H-NMR (300 MHz, DMSO-d₆, δ): 2.32 (3H, s), 4.54 (2H, s), 6.47(1H, d, J=16 Hz), 7.46. (2H, d, J=8 Hz), 7.48-7.56 (3H, m), 7.61 (2H, d,J=8 Hz), 7.74-7.81 (2H, m).

EXAMPLE 119

[2010] To a suspension of Compound E116 (147 mg) in ethanol (5 mL) wasadded 1N sulfuric acid (1.0 mL), and the mixture was stirred at 70° C.for 2 hours. The resulting precipitate was collected by filtration andwashed with ethanol to give Compound E119 (177 mg) as a white powder.

[2011]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.44 (2H, s), 6.46 (1H, d, J=16 Hz),7.39-7.49 (5H, m), 7.59 (2H, d, J=8 Hz), 7.67-7.71 (2H, m).

EXAMPLE 120

[2012] To a solution of Compound (6) (1.0 g),3-(benzyloxy)-1,2-benzenediamine (817 mg) and 1-hydroxybenzotriazole(567 mg) in N,N-dimethylformamide (19 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (804 mg).After stirring for 6 hrs, saturated aqueous NaHCO₃ (20 mL) and water (80mL) were added to the reaction mixture. The resulting precipitate wascollected by filtration and washed with water. To a mixture of thisproduct in acetic acid (7 mL) was added a solution of hydrogen chloridein acetic acid (13 mL). After stirring at 100° C. for 1 hour, theresulting mixture was cooled to 4° C. and diluted with ethyl acetate (40mL). The resulting precipitate was collected by filtration and washedwith ethyl acetate. To a solution of this product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (1.5 eq.) and1-hydroxybenzotriazole (1.5 eq.) in N,N-dimethylformamide (11 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.5 eq.) at 4° C.The mixture was warmed to ambient temperature and stirred for 8 hrs. Thereaction mixture was added saturated NaHCO₃ (11 mL) and water (44 mL). Aresulting precipitate was filtered and the filtrate was extracted withethyl acetate. The organic layer was washed with H₂O and brine, driedover MgSO₄, filtered and evaporated in vacuo. The crude product wastreated with trifluoroacetic acid to give Compound E120 (52 mg).

[2013]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.43 (2H, s), 6.46 (1H, d, J=16 Hz)6.86 (1H, d, J=8 Hz), 7.12(1H, d, J=8 Hz), 7.23-7.30 (1H, m), 7.39-7.62(5H, m);

[2014] MASS (ES+): m/z 310 (M+1).

EXAMPLE 121

[2015] To a solution of Compound (6) (1.0 g),4-(benzyloxy)-1,2-benzenediamine (817 mg) and 1-hydroxybenzotriazole(567 mg) in N,N-dimethylformamide (19 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (804 mg).After stirring for 6 hours, the reaction mixture were added saturatedNaHCO₃ (20 mL) and water (80 mL) The resulting precipitate was collectedby filtration and washed with water.

[2016] To a solution of this product in acetic acid (7 mL) was addedhydrogen chloride in acetic acid (13 mL). After stirring at 100° C. for1 hour, the resulting mixture was cooled to 4° C. and diluted with ethylacetate (40 mL). A resulting precipitate was collected by filtration andwashed with ethyl acetate. This product,O-tetrahydro-2H-pyran-2-ylhydroxylamine (1.5 eq.) and1-hydroxybenzotriazole (1.5 eq.) were dissolved in N,N-dimethylformamide(9 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.5 eq.) wasadded thereto at 4° C. The mixture was warmed to ambient temperature andstirred for 8 hours. To the reaction mixture were added saturated NaHCO₃(10 mL) and water (40 mL). The resulting precipitate was collected byfiltration and washed with water. The crude product was treated withhydrogen chloride in methanol to give Compound E121 (35 mg).

[2017]¹H-NMR (300 MHz, DMSO-d₆, δ): 4.52 (2H, s), 5.22 (2H, s), 6.49(1H, d, J=16 Hz), 7.21 (1H, dd, J=2, 8 Hz), 7.30(1H, d, J=2 Hz),7.34-7.50 (8H, m), 7.59 (2H, d, J=8 Hz), 7.67 (1H, d, J=8 Hz);

[2018] MASS (ES+): m/z 400 (M+1)

EXAMPLE 122

[2019] To a solution of Compound (51) (70 mg) in N,N-dimethylformamide(1.5 mL) was added N,N′-carbonyldiimidazole (40 mg). The mixture wasstirred for 30 min, and methanesulfonamide (24 mg) and1,8-diazabicyclo[5.4.0]-7-undecene (0.037 mL) were added thereto. Thereaction mixture was stirred for 8 hrs at 80° C. The resulting mixturewas acidified with 1 N hydrochloric acid at 0° C., and water (7.5 mL)was added thereto. The resulting precipitate was collected by filtrationand washed with water. The crude product was treated with hydrogenchloride in methanol to give Compound E122 (7.9 mg).

[2020]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.40 (3H, s), 4.46 (2H, s), 6.47(1H, d, J=16 Hz), 7.41-7.49 (3H, m), 7.58 (2H, d, J=8 Hz), 7.76 (1H, d,J=8 Hz), 7.95 (1H, d, J=8 Hz), 8.29 (1H, s);

[2021] MASS (ES+): m/z 415 (M+1).

EXAMPLE 123

[2022] To a suspension of Compound E116 (500 mg) in ethanol (5 mL) wasadded maleic acid (198 mg), and the mixture was stirred at 70° C. for 2hrs. The resulting precipitate was collected by filtration and washedwith ethanol and water. The solid was recrystallized from 50% aqueousEtOH to give Compound E123 (374 mg) as a pale yellow powder.

[2023]¹H-NMR (300 MHz, DMSO-₆, δ): 4.33 (2H, s), 6.17 (2H, s), 6.44 (1H,d, J=16 Hz), 7.24-7.32 (2H, m), 7.38-7.48 (3H, m), 7.53-7.62 (4H, m).

EXAMPLE 124

[2024] Compound E124 was obtained from Compound (260) according tomanners similar to Preparations 337 and 208 and Example 58 (7 mg).

[2025]¹H-NMR (300 MHz, DMSO-d₆, δ): 3.93 (2H, s), 4.18 (2H, s), 6.45(1H, d, J=16 Hz), 7.13 (1H, s), 7.23-7.38 (7H, m), 7.43 (1H, d, J=16Hz), 7.54 (2H, d, J=8 Hz);

[2026] MASS (ES+): m/z 334 (M+1).

[2027] The compounds obtained in the above-mentioned Preparations areshown in the following Table 2 (including Tables 2-1 to 2-44) and theabove-mentioned Examples are shown in the following Table 3 (includingTables 3-1 to 3-17). TABLE 2 Compound (1)

Compound (2)

Compound (3)

Compound (4)

Compound (5)

Compound (6)

Compound (7)

Compound (8)

Compound (9)

Compound (10)

Compound (11)

Compound (12)

Compound (13)

Compound (14)

Compound (15)

Compound (16)

Compound (17)

Compound (18)

Compound (19)

Compound (20)

Compound (21)

Compound (22)

Compound (23)

Compound (24)

Compound (25)

Compound (26)

Compound (27)

Compound (28)

Compound (29)

Compound (30)

Compound (31)

Compound (32)

Compound (33)

Compound (34)

Compound (35)

Compound (36)

Compound (37)

Compound (38)

Compound (39)

Compound (40)

Compound (41)

Compound (42)

Compound (43)

Compound (44)

Compound (45)

Compound (46)

Compound (47)

Compound (48)

Compound (49)

Compound (50)

Compound (51)

Compound (52)

Compound (53)

Compound (54)

Compound (55)

Compound (56)

Compound (57)

Compound (58)

Compound (59)

Compound (60)

Compound (61)

Compound (62)

Compound (63)

Compound (64)

Compound (65)

Compound (66)

Compound (67)

Compound (68)

Compound (69)

Compound (70)

Compound (71)

Compound (72)

Compound (73)

Compound (74)

Compound (75)

Compound (76)

Compound (77)

Compound (78)

Compound (79)

Compound (80)

Compound (81)

Compound (82)

Compound (83)

Compound (84)

Compound (85)

Compound (86)

Compound (87)

Compound (88)

Compound (89)

Compound (90)

Compound (91)

Compound (92)

Compound (93)

Compound (94)

Compound (95)

Compound (96)

Compound (97)

Compound (98)

Compound (99)

Compound (100)

Compound (101)

Compound (102)

Compound (103)

Compound (104)

Compound (105)

Compound (106)

Compound (107)

Compound (108)

Compound (109)

Compound (110)

Compound (111)

Compound (112)

Compound (113)

Compound (114)

Compound (115)

Compound (116)

Compound (117)

Compound (118)

Compound (119)

Compound (120)

Compound (121)

Compound (122)

Compound (123)

Compound (124)

Compound (125)

Compound (126)

Compound (127)

Compound (128)

Compound (129)

Compound (130)

Compound (131)

Compound (132)

Compound (133)

Compound (134)

Compound (135)

Compound (136)

Compound (137)

Compound (138)

Compound (139)

Compound (140)

Compound (141)

Compound (142)

Compound (143)

Compound (144)

Compound (145)

Compound (146)

Compound (147)

Compound (148)

Compound (149)

Compound (150)

Compound (151)

Compound (152)

Compound (153)

Compound (154)

Compound (155)

Compound (156)

Compound (157)

Compound (158)

Compound (159)

Compound (160)

Compound (161)

Compound (162)

Compound (163)

Compound (164)

Compound (165)

Compound (166)

Compound (167)

Compound (168)

Compound (169)

Compound (170)

Compound (171)

Compound (172)

Compound (173)

Compound (174)

Compound (175)

Compound (176)

Compound (177)

Compound (178)

Compound (179)

Compound (180)

Compound (181)

Compound (182)

Compound (183)

Compound (184)

Compound (185)

Compound (186)

Compound (187)

Compound (188)

Compound (189)

Compound (190)

Compound (191)

Compound (192)

Compound (193)

Compound (194)

Compound (195)

Compound (196)

Compound (197)

Compound (198)

Compound (199)

Compound (200)

Compound (201)

Compound (202)

Compound (203)

Compound (204)

Compound (205)

Compound (206)

Compound (207)

Compound (208)

Compound (209)

Compound (210)

Compound (211)

Compound (212)

Compound (213)

Compound (214)

Compound (215)

Compound (216)

Compound (217)

Compound (218)

Compound (219)

Compound (220)

Compound (221)

Compound (222)

Compound (223)

Compound (224)

Compound (225)

Compound (226)

Compound (227)

Compound (228)

Compound (229)

Compound (230)

Compound (231)

Compound (232)

Compound (233)

Compound (234)

Compound (235)

Compound (236)

Compound (237)

Compound (238)

Compound (239)

Compound (240)

Compound (241)

Compound (242)

Compound (243)

Compound (244)

Compound (245)

Compound (246)

Compound (247)

Compound (248)

Compound (249)

Compound (250)

Compound (251)

Compound (252)

Compound (253)

Compound (254)

Compound (255)

Compound (256)

Compound (257)

Compound (258)

Compound (259)

Compound (260)

Compound (261)

Compound (262)

Compound (263)

Compound (264)

Compound (265)

Compound (266)

Compound (267)

Compound (268)

Compound (269)

Compound (270)

Compound (271)

Compound (272)

Compound (273)

Compound (274)

Compound (275)

Compound (276)

Compound (277)

Compound (278)

Compound (279)

Compound (280)

Compound (281)

Compound (282)

Compound (283)

Compound (284)

Compound (285)

Compound (286)

Compound (287)

Compound (288)

Compound (289)

Compound (290)

Compound (291)

Compound (292)

Compound (293)

Compound (294)

Compound (295)

Compound (296)

Compound (297)

Compound (298)

Compound (299)

Compound (300)

Compound (301)

Compound (302)

Compound (303)

Compound (304)

Compound (305)

Compound (306)

Compound (307)

Compound (308)

Compound (309)

Compound (310)

Compound (311)

Compound (312)

Compound (313)

Compound (314)

Compound (315)

Compound (316)

Compound (317)

Compound (318)

Compound (319)

Compound (320)

Compound (321)

Compound (322)

Compound (323)

Compound (324)

Compound (325)

Compound (326)

Compound (327)

Compound (328)

Compound (329)

Compound (330)

Compound (331)

Compound (332)

Compound (333)

Compound (334)

Compound (335)

Compound (336)

Compound (337)

Compound (338)

Compound (339)

Compound (340)

[2028] TABLE 3 Compound E1

Compound E2

Compound E3

Compound E4

Compound E5

Compound E6

Compound E7

Compound E8

Compound E9

Compound E10

Compound E11

Compound E12

Compound E13

Compound E14

Compound E15

Compound E16

Compound E17

Compound E18

Compound E19

Compound E20

Compound E21

Compound E22

Compound E23

Compound E24

Compound E25

Compound E26

Compound E27

Compound E28

Compound E29

Compound E30

Compound E31

Compound E32

Compound E33

Compound E34

Compound E35

Compound E36

Compound E37

Compound E38

Compound E39

Compound E40

Compound E41

Compound E42

Compound E43

Compound E44

Compound E45

Compound E46

Compound E47

Compound E48

Compound E49

Compound E50

Compound E51

Compound E52

Compound E53

Compound E54

Compund E55

Compound E56

Compound E57

Compound E58

Compound E59

Compound E60

Compound E61

Compound E62

Compound E63

Compound E64

Compound E65

Compound E66

Compound E67

Compound E68

Compound E69

Compound E70

Compound E71

Compound E72

Compound E73

Compound E74

Compound E75

Compound E76

Compound E77

Compound E78

Compound E79

Compound E80

Compound E81

Compound E82

Compound E83

Compound E84

Compound E85

Compound E86

Compound E87

Compound E88

Compound E89

Compound E90

Compound E91

Compound E92

Compound E93

Compound E94

Compound E95

Compound E96

Compound E97

Compound E98

Compound E99

Compound E100

Compound E101

Compound E102

Compound E103

Compound E104

Compound E105

Compound E106

Compound E107

Compound E108

Compound E109

Compound E110

Compound E111

Compound E112

Compound E113

Compound E114

Compound E115

Compound E116

Compound E117

Compound E118

Compound E119

Compound E120

Compound E121

Compound E122

Compound E123

Compound E124

INDUSTRIAL APPLICABILITY

[2029] As mentioned above, the present invention can provide a novelcompound having a potent inhibitory effect on the activity of histonedeacetylase, and a pharmaceutical composition comprising the same. Thecompound is useful as an active ingredient of an immunosuppressant andan antitumor agent, and as an active ingredient of a therapeutic orprophylactic agent for diseases such as inflammatory disorders,diabetes, diabetic complications, homozygous thalassemia, fibrosis,cirrhosis, acute promyelocytic leukaemia (APL), organ transplantrejections, autoimmune diseases, protozoal infections, tumors, etc.

[2030] This application is based on the patent applications Nos.2003900116 and 2003905406, both were filed in Australia, and thecontents of which are incorporated hereinto by reference.

What is claimed is:
 1. A compound having the following formula (I):

wherein R¹ is N-containing heterocyclic ring optionally substituted withone or more suitable substituent(s), R² is hydroxyamino, R³ is hydrogenor a suitable substituent, L¹ is —(CH₂)_(n)— (wherein n is an integer of0 to 6) optionally substituted with one or more suitable substituent(s),wherein one or more methylene(s) may be replaced with suitableheteroatom(s), and L² is lower alkenylene, or a salt thereof.
 2. Thecompound of claim 1, wherein R¹ is N-containing heterocyclic ringrepresented by the following formula:

 wherein R⁴ is hydrogen or a group selected from the group consisting of(1) lower alkyl optionally substituted with di(lower)alkylamino orhydroxy, (2) lower alkoxy, (3) aryl optionally substituted with thesubstituent selected from the group consisting of halogen, loweralkanoyl, lower alkylsulfonyl, lower alkoxy and di(lower)alkylamino, (4)lower alkanoyl, (5) lower alkoxy-carbonyl, (6) arylcarbonyl, (7)aryl(lower)alkoxy, (8) amino optionally mono- or di-substitited withsubstituent(s) selected from the group consisting of lower alkyl, loweralkanoyl and cycloalkyl, (9) halo(lower)alkyl, (10) aryloxy, (11)aryl(lower)alkyl optionally substituted with hydroxy, (12) carboxyl,(13) nitro, (14) cyano, (15) halogen, (16) heteroaryl, (17) non-aromaticheterocycle optionally substituted with lower alkyl, (18) hydroxy, (19)(lower)alkylsulfonylcarbamoyl and (20) non-aromatic heterocyclecarbonyl, R⁵ is hydrogen or a group selected from the group consistingof lower alkyl and aryl(lower)alkyl, and R⁶, R⁷ and R⁸ are each hydrogenor lower alkyl, R⁹ is hydrogen or a group selected from the groupconsisting of (1) lower alkyl optionally substituted withdi(lower)alkylamino, (2) aryl optionally substituted with lower alkoxy,(3) (lower)alkoxy-carbonyl, (4) cyano, (5) carbamoyl optionally mono- ordi-substituted with (lower)alkyl, (6) halogen, (7)(lower)alkyl-carbonyl, (8) arylcarbonyl and (9) cyclo(lower)alkyl, R¹⁰is hydrogen or a group selected from the group consisting of (1)(lower)alkylcarbamoyl, (2) di(lower)alkylcarbamoyl, (3) aryl optionallysubstituted with halogen, (4) (lower)alkoxy-carbonyl, (5) carboxy, (6)non-aromatic heterocycle carbonyl, (7) halogen, (8) (lower)alkyloptionally substituted with hydroxy, (lower)alkoxy, non-aromaticheterocycle, aryl, di(lower)alkylamino or halogen and (9) adamantyl, R¹¹is hydrogen or aryl(lower)alkyl in which the aryl portion is substitutedwith lower alkoxy, R¹² is hydrogen or a group selected from the groupconsisting of lower alkyl and aryl optionally substituted with halogen,R¹³ is hydrogen or a group selected from the group consisting of loweralkyl and aryl, and R¹⁴ is hydrogen or lower alkyl, R² is hydroxyamino,R³ is hydrogen or lower alkoxy, L¹ is —(CH₂)_(n)— (wherein n is 1 to 5)optionally substituted with one or more substituent(s) selected fromlower alkyl(s) and aryl(lower)alkyl, and wherein one methylene may bereplaced with an oxygen atom, and L² is vinylene, or a salt thereof. 3.The compound of claim 2, wherein R¹ is N-containing condensedheterocyclic ring represented by the following formula:

 wherein R⁴ and R⁵ are each as defined in claim
 2. 4. The compound ofclaim 3, wherein R⁴ and R⁵ are each hydrogen, R² is hydroxyamino, R³ ishydrogen, L¹ is —CH₂—, and L² is vinylene, or a salt thereof.
 5. Thecompound of claim 2, wherein R¹ is N-containing heterocyclic ringrepresented by the following formula:

 wherein R⁹, R¹⁰ and R¹¹ are each as defined in claim
 2. 6. The compoundof claim 5, wherein R⁹ is hydrogen or aryl optionally substituted withlower alkoxy, R¹⁰ is hydrogen or aryl optionally substituted withhalogen, and R¹¹ is hydrogen, R² is hydroxyamino, R³ is hydrogen, L¹ is—CH₂—, and L² is vinylene, or a salt thereof.
 7. A compound of thefollowing formula

or a salt thereof.
 8. A compound having the following formula (I′):

wherein R¹ is N-containing condensed heterocyclic ring optionallysubstituted with one or more suitable substituent(s), R² ishydroxyamino, R³ is hydrogen or a suitable substituent, L¹ is—(CH₂)_(n)— (wherein n is an integer of 0 to 6) optionally substitutedwith one or more suitable substituent(s), wherein one or moremethylene(s) may be replaced with suitable heteroatom(s), and L² islower alkenylene, or a salt thereof.
 9. The compound of claim 8, whereinR¹ is N-containing condensed heterocyclic ring represented by thefollowing formula:

 wherein R⁴ is hydrogen or a group selected from the group consisting of(1) lower alkyl, (2) lower alkoxy, (3) aryl optionally substituted withthe substituent selected from the group consisting of halogen, loweralkanoyl, lower alkylsulfonyl, lower alkoxy and di(lower)alkylamino, (4)lower alkanoyl, (5) lower alkoxy-carbonyl, (6) arylcarbonyl, (7)aryl(lower)alkoxy, (8) amino optionally mono- or di-substitited withsubstituent(s) selected from the group consisting of lower alkyl, loweralkanoyl and cycloalkyl, (9) halo (lower)alkyl, (10) aryloxy, (11)aryl(lower)alkyl optionally substituted with hydroxy, (12) carboxyl,(13) nitro, (14) cyano, (15) halogen, (16) heteroaryl and (17)non-aromatic heterocycle optionally substituted with lower alkyl, R⁵ ishydrogen or a group selected from the group consisting of lower alkyland aryl(lower)alkyl, and R⁶, R⁷ and R⁸ are each hydrogen or loweralkyl, R² is hydroxyamino, R³ is hydrogen or lower alkoxy, L¹ is—(CH₂)_(n)— (wherein n is 1 or 2) optionally substituted with one ormore substituent(s) selected from lower alkyl(s) and aryl(lower)alkyl,and wherein one methylene may be replaced with an oxygen atom, and L² isvinylene, or a salt thereof.
 10. A compound having the following formula(I″):

wherein R¹ is N-containing condensed heterocyclic ring optionallysubstituted with one or more suitable substituent(s), R² ishydroxyamino, L¹ is —(CH₂)_(n)— (wherein n is an integer of 0 to 6)optionally substituted with one or more suitable substituent(s), and L²is lower alkenylene, or a salt thereof.
 11. The compound of claim 10,wherein R¹ is N-containing condensed heterocyclic ring represented bythe following formula:

 wherein R⁴ is hydrogen or a group selected from the group consisting oflower alkyl and aryl, and R⁵ is hydrogen or a group selected from thegroup consisting of lower alkyl and aryl(lower)alkyl, R² ishydroxyamino, L¹ is —(CH₂)_(n)— (wherein n is 1 or 2) optionallysubstituted with aryl(lower)alkyl, and L² is vinylene, or a saltthereof.
 12. A histone deacetylase inhibitor comprising the compound ofclaim
 1. 13. A pharmaceutical composition for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors, which comprises the compound of claim
 1. 14. A pharmaceuticalcomposition containing the compound of claim 1 as an active ingredient,in association with a pharmaceutically acceptable, substantiallynon-toxic carrier or excipient.
 15. The compound of claim 1 for use as amedicament.
 16. A method for inhibiting histone deacetylase, comprisingusing the compound of claim
 1. 17. A method for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors, which comprises administering an effective amount of thecompound of claim 1 to a human being or an animal.
 18. A commercialpackage comprising the pharmaceutical composition of claim 13 and awritten matter associated therewith, the written matter stating that thepharmaceutical composition may or should be used for treating orpreventing inflammatory disorders, diabetes, diabetic complications,homozygous thalassemia, fibrosis, cirrhosis, acute promyelocyticleukaemia (APL), organ transplant rejections, autoimmune diseases,protozoal infections or tumors.
 19. A histone deacetylase inhibitorcomprising the compound of claim
 7. 20. A pharmaceutical composition fortreating or preventing inflammatory disorders, diabetes, diabeticcomplications, homozygous thalassemia, fibrosis, cirrhosis, acutepromyelocytic leukaemia (APL), organ transplant rejections, autoimmunediseases, protozoal infections or tumors, which comprises the compoundof claim
 7. 21. A pharmaceutical composition containing the compound ofclaim 7 as an active ingredient, in association with a pharmaceuticallyacceptable, substantially non-toxic carrier or excipient.
 22. Thecompound of claim 7 for use as a medicament.
 23. A method for inhibitinghistone deacetylase, comprising using the compound of claim
 7. 24. Amethod for treating or preventing inflammatory disorders, diabetes,diabetic complications, homozygous thalassemia, fibrosis, cirrhosis,acute promyelocytic leukaemia (APL), organ transplant rejections,autoimmune diseases, protozoal infections or tumors, which comprisesadministering an effective amount of the compound of claim 7 to a humanbeing or an animal.
 25. A commercial package comprising thepharmaceutical composition of claim 20 and a written matter associatedtherewith, the written matter stating that the pharmaceuticalcomposition may or should be used for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors.
 26. A histone deacetylase inhibitor comprising the compoundof claim
 8. 27. A pharmaceutical composition for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors, which comprises the compound of claim
 8. 28. A pharmaceuticalcomposition containing the compound of claim 8 as an active ingredient,in association with a pharmaceutically acceptable, substantiallynon-toxic carrier or excipient.
 29. The compound of claim 8 for use as amedicament.
 30. A method for inhibiting histone deacetylase, comprisingusing the compound of claim
 8. 31. A method for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors, which comprises administering an effective amount of thecompound of claim 8 to a human being or an animal.
 32. A commercialpackage comprising the pharmaceutical composition of claim 27 and awritten matter associated therewith, the written matter stating that thepharmaceutical composition may or should be used for treating orpreventing inflammatory disorders, diabetes, diabetic complications,homozygous thalassemia, fibrosis, cirrhosis, acute promyelocyticleukaemia (APL), organ transplant rejections, autoimmune diseases,protozoal infections or tumors.
 33. A histone deacetylase inhibitorcomprising the compound of claim
 10. 34. A pharmaceutical compositionfor treating or preventing inflammatory disorders, diabetes, diabeticcomplications, homozygous thalassemia, fibrosis, cirrhosis, acutepromyelocytic leukaemia (APL), organ transplant rejections, autoimmunediseases, protozoal infections or tumors, which comprises the compoundof claim
 10. 35. A pharmaceutical composition containing the compound ofclaim 10 as an active ingredient, in association with a pharmaceuticallyacceptable, substantially non-toxic carrier or excipient.
 36. Thecompound of claim 10 for use as a medicament.
 37. A method forinhibiting histone deacetylase, comprising using the compound of claim10.
 38. A method for treating or preventing inflammatory disorders,diabetes, diabetic complications, homozygous thalassemia, fibrosis,cirrhosis, acute promyelocytic leukaemia (APL), organ transplantrejections, autoimmune diseases, protozoal infections or tumors, whichcomprises administering an effective amount of the compound of claim 10to a human being or an animal.
 39. A commercial package comprising thepharmaceutical composition of claim 34 and a written matter associatedtherewith, the written matter stating that the pharmaceuticalcomposition may or should be used for treating or preventinginflammatory disorders, diabetes, diabetic complications, homozygousthalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL),organ transplant rejections, autoimmune diseases, protozoal infectionsor tumors.